title: Orthogonal use of a human tRNA synthetase active site to achieve multifunctionality.
abstract: Protein multifunctionality is an emerging explanation for the complexity of higher organisms. In this regard, aminoacyl tRNA synthetases catalyze amino acid activation for protein synthesis, but some also act in pathways for inflammation, angiogenesis and apoptosis. It is unclear how these multiple functions evolved and how they relate to the active site. Here structural modeling analysis, mutagenesis and cell-based functional studies show that the potent angiostatic, natural fragment of human tryptophanyl-tRNA synthetase (TrpRS) associates via tryptophan side chains that protrude from its cognate cellular receptor vascular endothelial cadherin (VE-cadherin). VE-cadherin's tryptophan side chains fit into the tryptophan-specific active site of the synthetase. Thus, specific side chains of the receptor mimic amino acid substrates and expand the functionality of the active site of the synthetase. We propose that orthogonal use of the same active site may be a general way to develop multifunctionality of human tRNA synthetases and other proteins.
authors.affiliation: Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Zhou
authors.forename: Mili
authors.initials: M
authors.lastname: Kapoor
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.forename: Rajesh
authors.initials: R
authors.lastname: Belani
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.forename: William B
authors.initials: WB
authors.lastname: Kiosses
authors.forename: Melanie
authors.initials: M
authors.lastname: Hanan
authors.forename: Chulho
authors.initials: C
authors.lastname: Park
authors.forename: Eva
authors.initials: E
authors.lastname: Armour
authors.forename: Minh-Ha
authors.initials: MH
authors.lastname: Do
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Nangle
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D020134:Catalytic Domain; D006801:Humans; D047468:Immunoprecipitation; D008958:Models, Molecular; D016296:Mutagenesis; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D000604:Amino Acyl-tRNA Synthetases; D015703:Antigens, CD; D015820:Cadherins; D014364:Tryptophan; D000099152:Cadherin 5