Cytokine Receptors Fall Within Five Families

Receptors for the various cytokines are quite diverse structurally, but almost all belong to one of five families of receptor proteins (Figure 12-6):

■ Immunoglobulin superfamily receptors

■ Class I cytokine receptor family (also known as the hematopoietin receptor family)

■ Class II cytokine receptor family (also known as the interferon receptor family)

■ TNF receptor family

■ Chemokine receptor family

Many of the cytokine-binding receptors that function in the immune and hematopoietic systems belong to the class I cytokine receptor family. The members of this receptor family have conserved amino acid sequence motifs in the extracellular domain consisting of four positionally conserved cysteine residues (CCCC) and a conserved sequence of tryptophan-serine-(any amino acid)-tryptophan-serine (WSXWS, where X is the nonconserved amino acid). The receptors for all the cytokines classified as hematopoietins belong to the class I cytokine receptor family, which also is called the hematopoi-etin receptor family. The class II cytokine receptors possess the conserved CCCC motifs, but lack the WSXWS motif present in class I cytokine receptors. Initially only the three interferons, a, p, and 7, were thought to be ligands for these receptors. However, recent work has shown that the IL-10 receptor is also a member of this group.

Another feature common to most of the hematopoietin (class I cytokine) and the class II cytokine receptor families is

FIGURE 12-6

Schematic diagrams showing the structural features that define the five types of receptor proteins to which most cytokines bind. The receptors for most of the interleukins belong to the class I cytokine receptor family. C refers to conserved cysteine.

RECEPTOR FAMILY

(a) Immunoglobulin superfamily receptors

(a) Immunoglobulin superfamily receptors

(b) Class I cytokine receptors (hematopoietin)
Hematopoietin
(c) Class II cytokine receptors (interferon)
Class Cytokine Receptors
(d) TNF receptors

p

Cl

F

C3

B

C2

p

Cl

F

C3

6

C2

p

Cl

F

C3

B

C2

p

Cl

F

C3

C2

1

(e) Chemokine receptors

(e) Chemokine receptors

LIGANDS

IL-1

M-CSF

C-Kit

IL-E

IL-S

IL-4

IL-5

IL-6

IL-7

IL-9

IL-11

IL-lE

IL-13

IL-15

GM-CSF

G-CSF

CNTF

Growth hormone Prolactin

Nerve growth factor (NGF) FAS

IL-8

RANTES

MIP-l

MCAF

NAP-E

multiple subunits, often including one subunit that binds specific cytokine molecules and another that mediates signal transduction. Note, however, that these two functions are not always confined to one subunit or the other. Engagement of all of the class I and class II cytokine receptors studied to date has been shown to induce tyrosine phosphorylation of the receptor through the activity of protein tyrosine kinases closely associated with the cytosolic domain of the receptors.

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