Modular arrangement of extracellular regions and protein superfamilies

The extracellular regions of immune cell surface proteins include distinct domains which are often connected to the transmembrane domain by a linker or stalk region. Only one or two domains may have specific binding functions. Others may trigger oligomerization or ensure that binding domains are sufficiently distant from the membrane. Many extracellular protein modules belong to superfamilies. By definition, members of protein superfamilies share limited sequence similarity, often 30% or less, but similar three-dimensional structures. Table 1 includes structural prototypes of superfamilies determined to date. Some small domains found in different cell surface proteins consist of ß sheets or hairpins which may be arranged sandwich-like and stabilized by disulfide bonds.

Table 1 Three-dimensional structures of immune cell surface receptors and adhesion molecules

EGR6 FN type lao FN type 11*6

CD2 (domain 1)c CD2 (domains 1 + 2)c CD2 (domain 1, glycosylated)8 FN type III8-6" FN type III

FN type III (domains 7-10) hGH/hGHR" complex hGH/hPRLR" complex CCP (two domains)"'6 TNFR/TNFp complex TNFR NFcR

NFcR/Fc complex

E-selectin (C-type lectin + EGF domains) CD59 (glycosylated)3 Tissue factor"

Tissue factor/FVIIa complex

Integrin CD11b/CD18 (A domain, Mg2+ form)

Integrin CD11b/CD18 (A domain, Mn2' form)

cbEGF"-6

cbEGF (two domains) TCR (V(1 + Cp domains)1 TCR (V„ domain)0 IFN7/IFN7R« complex" E-Cadherin (domain 1)"" N-Cadherin (domain 1)" E-Cadherin (domains 1 + 2)" LM-EGF (three domains)6 TCR/MHC class I complex^ TCR/MHC class I complex11 EPOR/peptide complex" Link domain3 NCAM (domain I)« ICAM-2 (domains 1 + 2)c IL-1R/IL-1/3 complex* IL-1R/IL-1RA complex0 CD4 (domains 1-4) CD8a/MHC class I complex

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C, constant; CCP, complement control protein; C-type, calcium-dependent; EGF, epidermal growth factor; cbEGF, calcium-binding epidermal growth factor; EOPR, Erythropoietin receptor; FVIIa, blood coagulation factor Vila; Fc, antibody constant fragment; FN, fibronectin; hGH, human growth hormone; hGHR, human growth hormone receptor; hPRLR, human prolactin receptor; ICAM, intercellular adhesion molecule; IL-1R, interleukin-1 receptor; IL-1RA, interleukin-1 receptor antagonist; I FN, interferon; IFN-yRa, high-affinity interferon y receptor; LM-EGF, laminin-type EGF-like; NCAM, neural cell adhesion molecule; NFcR, neonatal fc receptor; TCR, T cell receptor; TNF, tumor necrosis factor: TNFR, tumor necrosis factor receptor; V, variable; VCAM-1, vascular cell adhesion molecule 1. "Structures determined by NMR.

"Small domains which occur in many cell surface or extracellular matrix proteins. "Immunoglobulin superfamily (IgSF) members. "Structurally similar to IgSF domains.

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