Lennarz W.J., Lane M.D. (eds.) Encyclopedia of Biological Chemistry. Four-Volume Set . V. 4

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Signal peptide

hTSHR

1 MRPADLLQLVLLLDLPRDLGG-- - 21

hFSHR

1 MALLLVSLLAFLSLGSG------- 17

hLHR

1 MKQRFSALQLLKLLLLLQPPLPRA 24

N-flanking Cysteine-rich sequence

hTSHR 22 ---MGC SSPPC E C HQEED - - FRVTC KDIQRI PSLPPSTQT- - - 56

hFSHR

18 -----

HHR I

SNRVFL-----

QESKVTEIPSDLPRNAI E 50

hLHR 25 L R E A L C P-EPC N C VPDG- - ALR- -C PGPTAGLTR--------- 53

Leucine-rich repeats

hTSHR 57 L KL I ETHLRT IPSHAFSNLPNISRI YVS I -DVTL QQLESHSFYNL SKVTHIEIRNTRNL T 115

hFSHR 51 L RFVLTKLRVIQKGAFSGFGDLEKIEISQNDV-L EV I EADVFSNL PKLHE I R IEKANNL L 109

hLHR 54 L SLAYLPVKV I PSQAFRGLNEVIKI E I SQIDS- L ER I EANAFDNL LNLSEI LIQNTKNL R 112

hTSHR 116 Y IDPDALKEL PLL KFLGI FNTGLKMFPDLTKVYSTDI FF I L E I T D N P Y M - T S I P V N A F Q G 174

hFSHR

110 Y I N P E A F Q N

QYLL I SNTGI KHLPD-VHK I HSLQKVL

DIQDNINIHT-IERNSFVG 167

hLHR 113 Y I E P G A F I N L PRL KYLS ICNTGIRKFPDVTKVFSSESNF I L E I CDNLH I TT - IPGNAFQG 171

hTSHR 175 L CNETLTL K L YNNGFTSVQGYAFNGTKL DAVYL NKNKYL TVIDKDAFGGVYSGPSLL D V S 234

hFSHR 168 L SFESVI L

NKNGIQEIHNCAFNGTQ

SDNNN

EELPNDVFHGASG-PVI

D I S 226

hLHR 172 M N N E S V T L K L YGNGFEEVQSHAFNGTTL TSL E L KENVHL EKMHNGAFRGATG-PKTL D I S 230

hTSHR

235 Q T S V T A

PSKG

IARNT

T L KKL PLSLSFLHL T R 274

hFSHR

227 R T R I H S

PSYG

RARSTYN

PTLEKLVA

M E 266

hLHR

231 S T K L Q A

PSYG

ESIQR

I ATSSYS

PSRETFVN

L E 270

C-flanking Cysteine-rich sequence

hTSHR

275 ADLSYPSH

AFKNQKKIRGILESL---------MCNESSMQSLRQRKSVNALNSPLHQE 325

hFSHR 267 ASLTYPSHCCAFAN

RRQI SEL -HP ICNKS I LRQEVDYMTQTRGQRSSLAE- - - - - - - - - 316

hLHR 271 A T L T Y P S H CCAFRNLPTKEQNFSHS---------ISENFSKQCESTVRKVS--------- 312

hTSHR

326 YEENLGDSIVGYKEKSKFQDTHNNAHYYVFFEEQEDEI IGFGQELKNPQEETLQAFDSHY 385

hFSHR 317 -----------------------------------------DNESSYS- -RGFDMTYTEF 333

hLHR

313 -----------------------------------------NKTLYSSMLAESELSG

D Y 331

hTSHR 386 D Y T I C GDSEDMVC TPKSDEFNPC EDI 411

hFSHR

334 D Y D L

NEVVDVT

SPKPDAFNP

EDI 359

hLHR 332 E Y G F C -LPKTPRC APEPDAFNPC ED I 356

FIGURE 1 Alignments of the amino acid sequences of the human TSHR, FSHR, and LHR. The deduced amino acid sequences for each of the three glycoprotein hormone receptors of human origin

are shown.

Transmembrane re

ion

I II

hTSHR 412 MGYKFLRIVV

FVSLLALLG

VFVLLILLTSHYKLNVPRFLMCN

AFA

F C M G M Y L L L I A 471

hFSHR

360 M G Y N I L R V L I

FISILAITG

I IVLV I LTTSQYKLTVPRFLMCN

AFA

LCIGIYLLLIA 419

hLHR

357 M G Y D F L R V L I

LINILAIMGN MTVLFVLLTSRYKLTVPRFLMCNL SFAD F C M G L Y L L L I A 416

III

hTSHR

472 SVDLYTHSEYYNHAID

QTGPGC NTAGFFTVFASELSVYTLTVITLER

YAI T F A M R L D R 531

hFSHR

420 SVDIHTKSQYHNYAID

QTGAGC DAAGFFTVFASELSVYTLTAI TLER

HT I T H A M Q L D C 479

hLHR 417 SVDSQTKGQYYNHA I D

QTGSGC STAGFFTVFASELSVYTLTVI TLER

HT I T Y A I H L D Q 476

IV V

hTSHR 532 KIRLRHACAIMVGG

VCCFL LALLPLVGI SSYAKVS ICLPMDTETPLALAYIVFVLTLNI 591

hFSHR 480 KVQLRHAASVMVMG

I FAFAAALFPI FGI SSYMKVSICLPMDIDSPLSQLYVMSLLVLNV 539

hLHR 477 K L R L R H A I L I M L G G

LFSSL IAMLPI VGVSNYMKVS ICFPMDVETTLSQVYILTILILNV 536

hTSHR

592 V A F V I V C C C

VK I Y I TVRNPQYNPGDKDTK I AKRMAVL I FTDF I CMA

I S F Y A L S A I L N K 651

hFSHR 540 L A F V V I C G C Y IHIYLTVRNPNIVSSSSDTRI AKRMAML I FTDFLCMAP I SFFA I SASLKV 599

hLHR 537 V A F F I I C A C Y IKIYFAVRNPELMATNKDTKIAKKMAILIFTDFTCMAP I SFFA I SASFKV 596

VII

hTSHR

652 PLITVSNSKI LLVLFYPLNSCA

AIFT 682

hFSHR 600 PL I TVSKAK I LLVLFHPINSCANPFLY AIFT 630

hLHR

597 PLITVTNSKVLLVLFYPINSCA

AIFT 627

Helix VIII

Hx VIII

hTSHR

683 KAFQRDVFI LLSKFGI

699

hFSHR 631 KNFRRDFF I LLSKCG-C 646

hLHR 628 K T F Q R D F F L L L S K F G C C 644

C terminus

hTSHR 700 KRQAQAYRGQRVPPKNSTD IQVQKVTHDMRQGLHNMEDVYEL IENSHLTPKKQGQISEEY 759

hFSHR

647 YEMQAQIYRTETSSTVHNTHPRNGHCSSAPRVTNGSTY I LVPLSHLAQN- - - - - - - - - - - 695

hLHR 645 KRRAELYRRKDFSAYTSNCKNGFTGSNKPSQSTLKLSTLHCQGTALLDKTRYTEC- - - - - 699

hTSHR 760 M Q T V L 764

hFSHR

-----

hLHR -----

Conserved cysteine Transmembrane domains Intracellular loops Extracellular loops

Conserved leucine Highly conserved residues within rhodopsin-like GPCRs

FIGURE 1 (continued)

Interestingly, the ligands for LGR7 and LGR8, relaxin

and/or Leydig cell insulin-like peptide, are structurally

homologous to insulin rather than to the glycoprotein

hormones.

Genomic Organization of the

Glycoprotein Hormone Receptors

The genes for these three receptors have a similar

structure. The LHR gene has 11 exons and the TSHR

and FSHR genes each have 10 exons. The last exon

codes for a small portion of the N-terminal extracellular

domain and all of the serpentine region, including the

C-terminal cytoplasmic tail. The other exons are small

and they are spliced together to form most of the

N-terminal extracellular domain.

The TSHR, LHR, and FSHR genes map to human

chromosomes 14q31, 2p21, and 2p21 –16, respectively.

Activation of the Glycoprotein

Hormone Receptors

GPROTEINS AND CELLULAR PATHWAYS

ACTIVATED BY THE GLYCOPROTEIN

HORMONE RECEPTORS

The identity of the G proteins activated by the FSHR has

not been directly examined. The TSHR has been shown

to activate all four families of G proteins and the LHR

activates at least three or perhaps all four families as

well. All of these receptors activate the cAMP and

inositol phosphate/diacylglycerol signaling cascades.

For each of the glycoprotein hormones, the EC

for

cAMP accumulation is lower than the EC

for inositol

phosphate accumulation. Moreover, activation of the

cAMP pathway is detectable even at low receptor

densities, whereas activation of the inositol phosphate/

diacylglycerol pathway is generally detectable only at

high receptor densities.

It is generally agreed that cyclic AMP is the principal

mediator of the actions of the glycoprotein hormones on

the differentiated functions of their target cells. The

functional consequences of the activation of the inositol

phosphate/diacylglycerol pathway are not fully under-

stood. In addition to controlling the differentiated

functions of target cells, the glycoprotein hormones

also control their proliferation. The three glycoprotein

hormones can each activate the extracellular regulated

kinase 1/2 cascade (ERK1/2) in their target cells and, at

least in the case of the LHR and the TSHR, this

activation seems to be mediated by cAMP.

MECHANISM OF ACTIVATION

Although it is clear that binding speciﬁcity is provided

by the large extracellular domains of the receptors and

the

-subunits of the hormones, little else is known

about how this event leads to receptor activation. Three

models have been proposed. In one model the common

-subunit of the glycoprotein hormones is thought to

directly interact with and activate the transmembrane

region of the receptor. In another model hormone

binding is thought to induce a conformational change

in the extracellular domain of the receptor,

thus allowing it to interact with and activate the

transmembrane region. The last model proposes that

the extracellular domain constrains a constitutive

activity intrinsic to the transmembrane domain

and that hormone binding to the extracellular

domain relieves this inhibition. This latter model has

received strong experimental support when tested with

the TSHR.

Naturally Occurring Mutations

of the Glycoprotein

Hormone Receptors

Both activating (gain-of-function) and inactivating

(loss-of-function) mutations of the glycoprotein hor-

mone receptor genes have been identiﬁed in patients

with particular endocrine disorders. Activating

mutations of these receptors results in the constitutive

activation and unregulated elevation of intracellular

cAMP in the absence of bound agonist. Most activating

mutations have been found in the serpentine regions

of the receptors; however, activating mutations of

the hTSHR have also been found in the extra-

cellular domain. Germ-line mutations resulting in

constitutive activation of the glycoprotein hormone

receptors are inherited in an autosomal dominant

manner.

Loss-of-function mutations refer to a number of

different types of mutations that ultimately cause

decreased target cell responsiveness to hormone.

These include mutations that impair coupling to

G protein, hormone binding, and/or cell surface

expression. The majority of loss-of-function mutations

of the glycoprotein hormone receptors result in

decreased cell surface expression of the mutant receptor

due to the intracellular retention of the misfolded

mutant. Therefore, loss-of-function mutations have

been identiﬁed in all regions of the glycoprotein

hormone receptors. Mutations of the glycoprotein

hormone receptors resulting in a loss-of-function are

inherited in an autosomal recessive manner.

184

TSH, LH AND FSH RECEPTORS

TSHR

A large number of activating mutations of the hTSHR

have been identiﬁed in individuals with autonomously

functioning thyroid adenomas (somatic mutations) or

autosomal dominant nonautoimmune hyperthyroidism

(germ-line mutations).

A number of loss-of-function hTSHR mutations have

been identiﬁed in individuals with nonautoimmune

congenital hypothyroidism, where the degree of

hypothyroidism correlates with the extent of target cell

unresponsiveness to TSH.

LHR

Numerous activating mutations of the hLHR have been

identiﬁed in boys with gonadotropin-independent pre-

cocious puberty (testotoxicosis). In these cases, the

constitutively active hLHRs inappropriately stimulate

testosterone production in Leydig cells under conditions

of prepubertal levels of LH. Only one hLHR mutation,

D578H, has been found to also cause Leydig cell

adenomas. Unlike the other hLHR activating mutations,

D578H was somatic rather than germ-line in origin.

Although it was initially postulated that D578H may

activate a pathway(s) different from those activated by

the other constitutively active hLHRs, such differences

have not yet been observed. Therefore, as with the

hTHSR, tumor formation by D578H may be due to its

somatic origin.

Many different loss-of-function hLHR mutations

have been identiﬁed in genetic males with micropenis

(partial loss-of-function) or pseudohermaphroditism

(severe loss-of-function). In the latter case, the individual

presents with female external genitalia but fails to

undergo breast development or menstruation at the time

of puberty. Female siblings with homozygous or

compound heterozygous loss-of-function LHR

mutations are infertile.

FSHR

Only one naturally occurring activating mutation of the

hFSHR has been reported. This mutation was found in a

hypophysectomized male receiving testosterone sup-

plementation who exhibited normal spermatogenesis.

Studies of this mutant in cell culture, however, have led

to disparate results on whether or not it is truly

activating. Surprisingly, activating FSHR mutations

have not been found in granulosa cell tumors examined

thus far. The paucity of naturally occurring activating

mutations of the hFSHR may reﬂect the lack of a readily

detectable pathophysiological state in males or females

arising from a constitutively active hFSHR and/or to the

relative resistance of the hFSHR to mutation-induced

constitutive activity.

The ﬁrst loss-of-function hFSHR mutation was

identiﬁed in a population of Finnish women with

primary amenorrhea due to ovarian failure. Cells

expressing the recombinant form of this hFSHR mutant

display no responsiveness to FSH. Surprisingly, men

homozygous for this mutation were not infertile,

although their fertility may have been impaired some-

what. Therefore, although FSH plays an important role

in spermatogenesis, these observations raised ongoing

debates regarding its absolute requirement. Since then,

other loss-of-function mutations of the hFSHR have

been identiﬁed in women with varying degrees of

FSH resistance.

FURTHER READING

Ascoli, M., Fanelli, F., and Segaloff, D. L. (2002). The lutropin/

choriogonadotropin receptor, a 2002 perspective. Endocr. Rev. 23,

141–174.

Davies, T., Marians, R., and Latif, R. (2002). The TSH receptor reveals

itself. J. Clin. Invest. 110, 161–164.

Hsu, S. Y., and Hsueh, A. J. (2000). Discovering new hormones,

receptors and signaling mediators in the genomic era. Mol.

Endocrinol. 14, 594–604.

Latronico, A., and Segaloff, D. L. (1999). Naturally occurring

mutations of the luteinizing-hormone receptor: Lessons learned

about reproductive physiology and G protein-coupled receptors.

Amer. J. Hum. Genet. 65, 949– 958.

Paschke, R., and Ludgate, M. (1997). The thyrotropin receptor in

thyroid diseases. N. Engl. J. Med. 337, 1675– 1681.

Rapoport, B., Chazenbalk, G. D., Jaume, J. C., and McLachlan, S. M.

(1998). The thyrotropin (TSH) receptor: Interaction with TSH and

autoantibodies. Endocr. Rev. 19, 673–716.

Simoni, M., Gromoll, J., and Nieschlag, E. (1997). The follicle-

stimulating hormone receptor: Biochemistry, molecular biology,

physiology, and pathophysiology. Endocr. Rev. 18, 739–773.

TSH, LH AND FSH RECEPTORS 185

Themmen, A. P. N., and Huhtaniemi, I. T. (2000). Mutations of

gonadotropins and gonadotropin receptors: Elucidating the physi-

ology and pathophysiology of pituitary-gonadal function. Endocr.

Rev. 21, 551–583.

BIOGRAPHY

Deborah L. Segaloff is a Professor of Physiology and Biophysics and

Mario Ascoli a Professor of Pharmacology in the Roy J. and Lucille

A. Carver College of Medicine at the University of Iowa in Iowa City,

Iowa Dr. Segaloff’s laboratory cloned the cDNA for the rat LHR, the

ﬁrst glycoprotein hormone receptor to be cloned. Since then, Dr.

Segaloff’s and Dr. Ascoli’s laboratories have performed extensive

studies on the regulation and the mechanisms of activation and

desensitization of the gonadotropin receptors.

Dario Mizrachi is a Postdoctoral Associate in Dr. Segaloff’s laboratory.

As a Lalor Fellow, Dr. Mizrachi developed homology models of the

glycoprotein hormone receptors for use in predicting the structural

arrangements of the receptors.

186 TSH, LH AND FSH RECEPTORS

Tight Junctions

Shoichiro Tsukita

Kyoto University, Kyoto, Japan

The tight junction (TJ) or zonula occludens is one mode of

cell-to-cell adhesion in vertebrate epithelial and endothelial

cellular sheets, and is located at the most apical part of their

lateral membranes. The existence of separate ﬂuid compart-

ments with different molecular compositions is of particular

importance for the development and maintenance of multi-

cellular organisms. These compartments are delineated by

various cellular sheets, which function as barriers to maintain

the distinct internal environment of each compartment. Within

these sheets, individual cells are mechanically linked to each

other to maintain the structural integrity of the sheet, and the

intercellular space between adjacent cells is sealed to prevent

the diffusion of solutes through the intercellular space. TJs are

directly involved in this intercellular sealing.

Structure

ELECTRON MICROSCOPIC IMAGE

On ultrathin section electron microscopy, tight junctions

(TJs) appear as a zone where plasma membranes of

neighboring cells focally make complete contact

(Figure 1D). On freeze-fracture electron microscopy,

TJs are visualized as a continuous, anastomosing

network of intramembranous particle strands

(TJ strands or ﬁbrils) and complementary grooves.

THREE-DIMENSIONAL IMAGE

Detailed electron microscopic observations led to our

current understanding of the three-dimensional

structure of TJs (Figure 1C); each TJ strand is associated

laterally with another TJ strand in apposing membranes

of adjacent cells to form “paired” TJ strands, where the

intercellular space is completely obliterated.

Molecular Architecture

INTEGRAL MEMBRANE PROTEINS

Three distinct types of integral membrane proteins are

localized at TJs: claudin, occludin, and JAM (Figure 2).

Claudin with a molecular mass of , 23 kDa is a major

constituent of TJ strands, and bears four transmembrane

domains. In mice and humans, claudins comprise a

multigene family consisting of 24 members. When each

claudin species is overexpressed in mouse ﬁbroblasts,

claudin molecules are polymerized within the plasma

membranes to reconstitute paired TJ strands. As many

distinct species of claudins are coexpressed in individual

cells, heterogeneous claudin species are copolymerized

to form individual TJ strands as heteropolymers, and

between adjacent TJ strands claudin molecules adhere to

each other in both homotypic and heterotypic manners,

except in certain combinations.

Occludin, a , 65 kDa integral membrane protein,

also bears four transmembrane domains, but does not

show any sequence similarity to claudins. Occludin is

incorporated in TJ strands in situ, but TJ strands can be

formed without occludin. JAM with a single trans-

membrane domain associates laterally with TJ strands,

while not constituting the strands per se. The physio-

logical functions of occludin and JAM remain elusive.

PERIPHERAL MEMBRANE PROTEINS

Claudins are packed densely within the TJ strands.

Therefore, their cytoplasmic surface appears similar to a

brush consisting of numerous short carboxyl-terminal

cytoplasmic tails of claudins. Interestingly, most of

these tails end in valine at their carboxyl termini,

suggesting that these carboxyl termini directly bind to

PDZ domains. Therefore, the cytoplasmic surface of

TJ strands can be regarded as a magnetic bar that

strongly attracts and recruits many PDZ-containing

proteins.

Indeed, three related PDZ-containing proteins,

ZO-1 (, 220 kDa), ZO-2 (, 160 kDa), and ZO-3

(, 130 kDa), are concentrated at TJs. These molecules

all have three PDZ domains (PDZ1 to 3), one SH3

domain, and one GUK (guanylate kinase-like) domain in

this order from their NH

-termini indicating that they

belong to membrane-associated guanylate kinase-like

homologues (MAGUKs). Among these three PDZ

domains, PDZ1 domain binds directly to the COOH

termini of claudins.

In addition to these three TJ-speciﬁc MAGUKs,

several other PDZ-containing proteins are recruited to

the cytoplasmic surface of TJ strands. These proteins are

multidomain proteins, and may function as adapters at

the cytoplasmic surface of TJs together with non-

MAGUK proteins such as cingulin and symplekin,

which recruit various proteins including cytoskeletal as

well as signaling molecules.

Functions

BARRIER FUNCTION

Claudins are directly involved not only in the formation

of TJ strands but also in their barrier function in simple

epithelia, not only for solutes but also for pathogens

such as bacteria. Furthermore, TJs are not simple

barriers; they show ion and size selectivity and their

barrier function varies signiﬁcantly in tightness depend-

ing on the cell-type and physiological requirements. Such

regulated and diversiﬁed permeability of TJs is required

for dynamically maintaining the environment of each

compartment. To explain the material transport across

TJs, aqueous pores (or paracellular channels) have been

postulated to exist within paired TJ strands. It is now

widely believed that the combination and mixing ratios

of claudins within individual paired strands determine

the tightness and selectivity of these aqueous pores.

FENCE FUNCTION

TJ strands are heteropolymers of integral membrane

proteins, claudins, within plasma membranes, and

continuously encircle the top of individual epithelial/

endothelial cells to delineate the border between the

apical and basolateral membrane domains. Therefore, it

is believed that TJ strands act as a “fence,” limiting the

lateral diffusion of lipids and proteins between the apical

and basolateral membrane domains. Indeed, when

ﬂuorescently labeled lipids are inserted into the outer

leaﬂet of the apical membrane of cultured epithelial cells,

these lipids are retained on the apical surface. In contrast,

the importance of TJs in the asymmetric distribution of

integral membrane proteins remains controversial.

OTHER POSSIBLE FUNCTIONS

As previously mentioned, various types of proteins

including PDZ-containing proteins are recruited to the

cytoplasmic surface of TJ strands to form a huge

macromolecular complex. This macromolecular com-

plex is expected to play central roles in the intracellular

signaling of epithelial cells, being involved in the

regulation of their proliferation and morphogenesis,

i.e., contact inhibition of cell growth and epithelial cell

polarization, respectively.

FURTHER READING

Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P.

(2002). Molecular Biology of the Cell. Garland Publishing,

New York.

Cereijido, M., and Anderson, J. (2001). Tight Junctions. CRC Press,

New York.

Gonzalez-Mariscal, L., Betanzos, A., Nava, P., and Jaramillo, B. E.

(2003). Tight junction proteins. Prog. Biophys. Mol. Biol. 81,

1–44.

Schneeberger, E. E., and Lynch, R. D. (1992). Structure, function, and

regulation of cellular tight junctions. Am. J. Physiol. 262,

L647–L661.

Tsukita, Sh., Furuse, M., and Itoh, M. (2001). Multifunctional strands

in tight junctions. Nat. Rev. Mol. Cell. Biol. 2, 285–293.

BIOGRAPHY

Shoichiro Tsukita is a Professor in the Department of Cell Biology at

Kyoto University, Kyoto, Japan. His principal research interests are in

cell–cell adhesion and cytoskeletons. He holds M.D. and Ph.D. from

the University of Tokyo. His group established a new isolation

procedure for intercellular junctions and identiﬁed occludin and

claudins.

TIGHT JUNCTIONS 189

Toll-Like Receptors

Himanshu Kumar, Kiyoshi Takeda and Shizuo Akira

Osaka University, Osaka, Japan

Toll-like receptors (TLRs) are the family of receptor molecules

that recognizes microbe-speciﬁc conserved molecular motifs.

Recognition of these molecular motifs by innate cells of innate

immune system activates downstream signaling cascades to

induce secretion of cytokines, chemokines, and expression of

costimulatory molecules. These effects subsequently instruct

the major component of adaptive immune system that is B and

T cells to exhibit pathogen-speciﬁc antimicrobial activity. At

the end of the twentieth century, this family of receptors has

been discovered and till date ten TLR molecules are known.

Innate Immune System

Innate immunity acts as the ﬁrst line of host defense

against microbial pathogens. It is conserved from ﬂies to

mammals. Innate immunity is dependent on both

cellular components such as monocytes, macrophages,

neutrophils, dendritic cells, and endothelial cells, and

humoral components such as C-reactive protein (CRP),

lysozyme, and complements. The cellular component of

innate immunity recognizes a wide range of pathogen-

associated molecular motifs by virtue of pattern

recognition receptors (PRR). There are two types of

PRRs. One type of PRRs, such as CR3 and C-type

lectins, facilitate receptor-mediated phagocytosis. Other

PRRs, such as TLRs, trigger the activation of innate

immunity. It has recently been shown that toll-like

receptor (TLRs) are the most important PRRs in

triggering the activation of innate immunity.

TLRs and their Ligands

Toll receptor was ﬁrst described in context of the dorso-

ventral development of Drosophila embryo. Toll and its

mammalian homologues (TLRs) are type I membrane

proteins, harboring an ectodomain consisting of leucine-

rich repeats (LRRs) and one or two cysteine rich regions.

The intracellular domain of toll receptors is structurally

similar to that of the IL-1 receptor. Therefore, it is called

Toll/IL-1R (TIR) domain. This region of TLRs is

required for homophilic and heterophilic interaction of

TLRs. The TIR domain further interacts with several

TIR domain-containing adaptors such as MyD88,

TIRAP/Mal, and TRIF. To date, ten TLRs (TLR1–10)

have been identiﬁed and shown to recognize different

classes of pathogen-derived molecular motifs (Table I).

Distribution of TLRs

Distribution of these TLR molecules in different cells

and tissue type is shown in Table II.

Intracellular Signal Transduction

through TLR

The molecular mechanisms by which TLRs trigger

activation of innate immunity have been elucidated

through analysis of signaling pathways. Intracellular

signal transduction initiates from the TIR domain of

TLRs. The TIR domain of TLRs interacts with the TIR

domain (present in the C terminus) of MyD88 adaptor

protein. MyD88 contains a death domain at the N

terminus. When ligands are bound to TLRs, MyD88

recruits IRAK to TLRs through the interaction of death

domains and leads to phosphorylation of IRAK, which

has serine/threonine kinase activity. IRAK then binds

TRAF-6 to form the IRAK–TRAF6 complex. This

complex activates the NF

B transactivator that induces

transcription of inﬂammatory cytokine genes. This

complex also activates the JNK pathway and generates

the active AP-1 transactivator as shown in Figure 1.In

addition to this MyD88-mediated component of signal-

ing pathway, a MyD88-independent component leading

to IFN-

production has been identiﬁed in TLR3 and

TLR4 signaling pathways.

MYD88-DEPENDENT

SIGNALING PATHWAY

Stimulation of MyD88-deﬁcient macrophages with

known TLR ligands induced no production of inﬂamma-

tory cytokines. This indicates that MyD88 plays a pivotal

role in the TLR-mediated production of inﬂammatory

TABLE I

Description of Toll-Like Receptor

TLR Gene (Human) Functional receptor Ligands of TLR Immune response

TLR1 4p14 Heterodimers of TLR2-TLR1 Tri-acyl lipopeptides (bacteria, Mycobacteria), soluble factors,

Neisseria meningitis

Induce secretion of inﬂammatory

cytokine(s)

TLR2 4q32 Heterodimers of TLR2-TLR1

and heterodimer of TLR2-TLR6

Lipoprotein/lipopeptides (different pathogen),

peptiodoglycan (gram-positive bacteria),

lipoteichoic acid (gram-positive bacteria),

lipoarabinomannan (Mycobacteria),

a phenol soluble modulin (Staphylococcus aureus),

glycoinositolphospholipids

(Trypanosoma cruzi), glycolipid (Treponema maltophilum),

porins (Neisseria), zymosan (fungi), HSP70 (host),

atypical LPS (Leptospira interrogans), atypical LPS

(Porphyromonas gingivalis)

Induce secretion of inﬂammatory

cytokine(s)

TLR3 4q35 Not known Double-stranded RNA (mainly from virus) Induce type I interferon (IFN-

/IFN-

)

TLR4 9q32-33 LPS-LPS binding protein complex

associate with CD14 and MD-2,

in B-cell TLR4 associate with

RP105 and MD-1

LPS (gram-negative bacteria, taxol (plant), HPS60 (host),

HPS70 (host), fusion protein (RSV),

HPS60 (Chlamydia pneumoniae), ﬁbronectin (host),

envelope proteins (MMTV), type III repeat

extra domain A of ﬁbronectin (host), oligosaccharides

of hyaluronic acid (host), polysaccharides fragments

of heparin sulfate (host) and ﬁbrinogen (host)

Induce secretion of inﬂammatory

cytokine(s) and chemokines

TLR5 1q33.3 Not known 55 kDa monomer obtained from bacteria ﬂagella (ﬂagellin) Induce inﬂammatory cytokine(s)

TLR6 4p14 Heterodimer of TLR2-TLR6 Di-acyl lipopeptides (mycoplasma) Induce secretion of inﬂammatory

cytokine(s)

TLR7 Xp22 Not known Synthetic compounds like imidazoquinoline

(imquimod (R-848), resiquimod (R848)),

loxoribine and bropirimine

Induce secretion of inﬂammatory

cytokine(s)

TLR8 Xp22 Not known Ligand(s) not known Not known

TLR9 3p21.3 TLR9 (localized in endosomal

compartment)

Unmethylated CpG DNA (Mycobacteria and Bacteria) Activate Th1 type immune

response, Induce proliferation

of B-cell, activate macrophage

and DCs

TLR10 Not known Not known Ligand(s) not known Not known