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Modelling of the ABL and ARG proteins predicts two functionally critical regions that are natively unfolded
Author(s) -
Buffa Pietro,
Manzella Livia,
Consoli Maria Letizia,
Messina Angelo,
Vigneri Paolo
Publication year - 2007
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21161
Subject(s) - sh3 domain , sh2 domain , tyrosine kinase , abl , hamp domain , microbiology and biotechnology , proto oncogene tyrosine protein kinase src , biology , protein kinase domain , receptor tyrosine kinase , protein domain , tyrosine , phosphorylation , chemistry , binding domain , biochemistry , binding site , signal transduction , gene , mutant
The ABL and ARG tyrosine kinases regulate many pivotal cellular processes and are implicated in the pathogenesis of several forms of leukemia. We have modelled the previously uncharacterized core domain (SH3‐SH2‐tyrosine kinase) and C‐terminal actin‐binding domain of ARG. We have also investigated the structural arrangement of the ABL and ARG Cap region and of the long multifunctional region located downstream of the tyrosine kinase domain. We report that the ARG core domain is homologous to the corresponding ABL region, therefore suggesting that ARG catalytic activity is likely regulated by the same SH3–SH2 clamp described for ABL. We also report that the Cap of both ABL and ARG is natively unfolded. Hence, biological events determining the folding of the Cap are critical to allow its interaction with the tyrosine kinase C‐lobe. Furthermore, our results show that, with the exception of the C‐terminal actin‐binding domain, the entire region encoded by the ABL and ARG last exon is natively unfolded. Phosphorylation events or protein–protein interactions regulating the folding of this region will therefore modulate the activity of its numerous functional domains. Finally, our analyses show that the C‐terminal actin‐binding domain of ARG displays a four‐helix bundle structure similar to the one reported for the corresponding ABL region. Our findings imply that many biological activities attributed to ABL, ARG, and their oncogenic counterparts are regulated by natively unfolded regions. Proteins 2007. © 2007 Wiley‐Liss, Inc.