Evolution of SH2 domains

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SH2 domains are widespread in metazoans and choanoflagellates, along with their cognate tyrosine kinases, but are also found in several other lineages. In particular, the Spt6 gene is found in most eukaryotes, including plants and excavates and is known to bind pSer rather than pTyr. The Spt6 structure confirms pSer specificity, and notes that it is intermediate between the two major classes (STAT and Src) of SH2 domain (2). The phylogeny and structure suggest that this may be the primordial SH2 domain.

There is a restricted family of clear SH2 domains in plants (3), with two similar members in Arabidopsis (SHA and SHB), and one in most other vascular plants and moss. The large family of plant GRAS proteins has also been proposed to be STAT homologs and contain SH2 domains (4). However, there is no significant overall sequence similarity in our hands between GRAS and SH2, even using profile-profile comparisons, and secondary structure prediction (JPred) also suggests that the proposed domain in GRAS does not fold like an SH2.

HMM profiles show no SH2 domains other than Spt6 in algae, excavates or fungi. However, Dictyostelium has about 14 SH2 domains, several linked to STATs or to TKL group kinases, strongly suggesting that they bind phosphotyrosine. The loosely related Entamoeba histolytica also has SH2 domains, with 6 fused to kinases and homologous to Dictyostelium genes, and another two having no other domains (but are most similar to the Entamoeba kinases).

Apart from Spt6, and Dictyostelium STAT, the earliest SH2 proteins with human homologs are found in the choanoflagellate, Monosiga brevicollis. It has 123 SH2 proteins, including members of 15 classes and all 11 major functional categories found in human SH2 proteins (5).


(1) Yoh, SM, Cho, H, Pickle, L, Evans, RM, Jones, KA (2007).The Spt6 SH2 domain binds Ser2-P RNAPII to direct Iws1-dependent mRNA splicing and export. Genes & Dev. 21: 160-74. PMID 17234882

(2) Dengl, S, Mayer, A, Sun, M, Cramer, P (2009) Structure and in Vivo Requirement of the Yeast Spt6 SH2 Domain. J. Mol. Biol. 289:211-25. PMID 19371747

(3) Williams, JG, Zvelebil, M. (2004) SH2 domains in plants imply new signalling scenarios. Trends in Plant Science 9: 161-163. PMID 15063865

(4) Richards, DE, Peng, J, Harberg, N (2000). Plant GRAS and metazoans STATs: one family? BioEssays 22:57-7. PMID 10842311

(5) Manning, G, Young, SL, Miller, WT, Zhai, Y. (2008) The protist, Monosiga brevicollis, has a tyrosine kinase signaling network more elaborate and diverse than found in any known metazoan. PNAS 105:9674-9. PMID 18621719