Songyang Z, Gish G, Mbamalu G, Pawson T, Cantley L C
Division of Signal Transduction, Beth Israel Hospital, Boston, Massachusetts, USA.
J Biol Chem. 1995 Nov 3;270(44):26029-32. doi: 10.1074/jbc.270.44.26029.
Src homology 2 (SH2) domains recognize phosphotyrosine-containing sequences, and thereby mediate the association of specific signaling proteins in response to tyrosine phosphorylation (Pawson, T., and Schlessinger, J. (1993) Curr. Biol. 3, 434-442). We have shown that specific binding of SH2 domains to tyrosine-phosphorylated sites is determined by sequences adjacent to the phosphotyrosine. Based on the phosphopeptide specificity and crystal structures, SH2 domains were classified into four different groups (Songyang, Z., Shoelson, S. E., Chaudhuri, M., Gish, G., Pawson, T., Haser, W. G., King, F., Roberts, T., Ratnofsky, S., Lechleider, R. J., Neel, B. G., R. B. B., Fajardo, J. E., Chou, M. M., Hanafusa, H., Schaffhausen, B., and Cantley, L. C. (1993) Cell 72, 767-778). The beta D5 residues of SH2 domains were predicted to be critical in distinguishing these groups (Songyang, Z., Shoelson, S. E., Chaudhuri, M., Gish, G., Pawson, T., Haser, W. G., King, F., Roberts, T., Ratnofsky, S., Lechleider, R. J., Neel, B. G., R. B. B., Fajardo, J. E., Chou, M. M., Hanafusa, H., Schaffhausen, B., and Cantley, L. C. (1993) Cell 72, 767-778; Eck, M. J., Shoelson, S. E., and Harrison, S. C. (1993) Nature 362, 87-91). We report here that replacing the aliphatic residues at the beta D5 positions of two Group III SH2 domains (phosphoinositide 3-kinase N-terminal SH2 domain and phospholipase C-gamma C-terminal SH2 domain) with Tyr (as found in Group I SH2 domains) results in a switch in phosphopeptide selectivity, consistent with the specificities of Group I SH2 domains. These results establish the importance of the beta D5 residue in determining specificities of SH2 domains.
Src同源2（SH2）结构域识别含磷酸酪氨酸的序列，从而介导特定信号蛋白在酪氨酸磷酸化时的结合（帕森斯，T.，和施莱辛格，J.（1993年）《当代生物学》3，434 - 442）。我们已经表明，SH2结构域与酪氨酸磷酸化位点的特异性结合由磷酸酪氨酸附近的序列决定。基于磷酸肽特异性和晶体结构，SH2结构域被分为四个不同的组（宋阳，Z.，肖尔森，S.E.，乔杜里，M.，吉什，G.，帕森斯，T.，哈泽，W.G.，金，F.，罗伯茨，T.，拉特诺夫斯基，S.，莱克莱德，R.J.，尼尔，B.G.，R.B.B.，法亚尔多，J.E.，周，M.M.，花房，H.，沙夫豪森，B.，和坎特利，L.C.（1993年）《细胞》72，767 - 778）。预测SH2结构域的βD5残基在区分这些组中起关键作用（宋阳，Z.，肖尔森，S.E.，乔杜里，M.，吉什，G.，帕森斯，T.，哈泽，W.G.，金，F.，罗伯茨，T.，拉特诺夫斯基，S.，莱克莱德，R.J.，尼尔，B.G.，R.B.B.，法亚尔多，J.E.，周，M.M.，花房，H.，沙夫豪森，B.，和坎特利，L.C.（1993年）《细胞》72，767 - 778；埃克，M.J.，肖尔森，S.E.，和哈里森，S.C.（1993年）《自然》362，87 - 91）。我们在此报告，将两个III组SH2结构域（磷脂酰肌醇3激酶N端SH2结构域和磷脂酶CγC端SH2结构域）的βD5位置的脂肪族残基替换为酪氨酸（如I组SH2结构域中所见）会导致磷酸肽选择性的转变，这与I组SH2结构域的特异性一致。这些结果确立了βD5残基在决定SH2结构域特异性方面的重要性。
