title: The intertwining of structure and function: proposed helix-swapping of the SH2 domain of Grb7, a regulatory protein implicated in cancer progression and inflammation.
abstract: Grb7 is a multidomain intracellular signaling protein that links activated tyrosine kinases with downstream signaling targets. Best known for its regulatory role in cell migration and tumor metastasis, Grb7 also regulates inflammation by coupling NF-kappaB-inducing kinase with erbB/EGFR family receptors. The "adaptor" role of Grb7 in these processes depends upon binding to membrane-associated tyrosine kinases through its C-terminal SH2 domain. The Grb7-SH2 domain shares structural and functional similarity with the SH2 domain of Grb2, a constituent of the MAP kinase pathway. Both domains show unusual affinity for cyclic (beta-turn) ligands. The Grb2-SH2 domain also shows distinctive self-association behavior, forming intertwined ("swapped") dimers. While Grb7 and its SH2 domain are each known to dimerize, the mechanisms and functional significance of this self-association are incompletely understood. Additional residues in the Grb7-SH2 domain effectively lengthen its "EF loop" and render the domain a good candidate for swapped dimerization, through exchange of a C-terminal helix. We propose the existence of a swapped dimeric form of the Grb7-SH2 domain and offer a structural model derived through novel application of nuclear magnetic resonance-derived restraints.
authors.affiliation: Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003-8001, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Pias
authors.forename: Tabitha A
authors.initials: TA
authors.lastname: Peterson
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Johnson
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Lyons
mesh_terms: D018450:Disease Progression; D051382:GRB7 Adaptor Protein / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D013329:Structure-Activity Relationship; D018909:src Homology Domains
chemical_list: C495955:GRB7 protein, human; D051382:GRB7 Adaptor Protein