Structural determinants of integrin β-subunit specificity for latent TGF-β
Structural determinants of integrin β-subunit specificity for latent TGF-β
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DOI：
10.1038/nsmb.2905
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发表时间：
2014-12-01
影响因子：
16.8
通讯作者：
Springer, Timothy A.
中科院分区：
文献类型：
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作者：
Dong, Xianchi;Hudson, Nathan E.;Springer, Timothy A.
八种整联蛋白α-β异二聚体识别具有Arg-Gly-Asp（RGD）基序的配体。然而，整合素在具有RGD基序的细胞外蛋白中分化的结构机制尚不清楚。晶体结构、突变和肽亲和力测量显示，α（v）β（6）以高亲和力结合TGF-β 1和TGF-β 3的前结构域内的RGDLXXL/I基序。LXXL/I基序形成结合在β（6）亚基中的疏水口袋中的两亲性α-螺旋。通过整联蛋白β亚基阐明配体结合特异性的基础揭示了三种不同β I结构域环的贡献，我们将其命名为特异性决定环（SDLs）1、2和3。SDL 1和SDL 3中一对单一关键残基的变异与整联蛋白进化中整个β亚基的变异相关，从而表明在整个β亚基功能中的典范作用。
Eight integrin alpha-beta heterodimers recognize ligands with an Arg-Gly-Asp (RGD) motif. However, the structural mechanism by which integrins differentiate among extracellular proteins with RGD motifs is not understood. Here, crystal structures, mutations and peptide-affinity measurements show that alpha(v)beta(6) binds with high affinity to a RGDLXXL/I motif within the prodomains of TGF-beta 1 and TGF-beta 3. The LXXL/I motif forms an amphipathic alpha-helix that binds in a hydrophobic pocket in the beta(6) subunit. Elucidation of the basis for ligand binding specificity by the integrin beta subunit reveals contributions by three different beta I-domain loops, which we designate specificity-determining loops (SDLs) 1, 2 and 3. Variation in a pair of single key residues in SDL1 and SDL3 correlates with the variation of the entire beta subunit in integrin evolution, thus suggesting a paradigmatic role in overall beta-subunit function.