title: NMR structure and mutagenesis of the N-terminal Dbl homology domain of the nucleotide exchange factor Trio.
abstract: Guanine nucleotide exchange factors for the Rho family of GTPases contain a Dbl homology (DH) domain responsible for catalysis and a pleckstrin homology (PH) domain whose function is unknown. Here we describe the solution structure of the N-terminal DH domain of Trio that catalyzes nucleotide exchange for Rac1. The all-alpha-helical protein has a very different structure compared to other exchange factors. Based on site-directed mutagenesis, functionally important residues of the DH domain were identified. They are all highly conserved and reside in close proximity on two a helices. In addition, we have discovered a unique capability of the PH domain to enhance nucleotide exchange in DH domain-containing proteins.
authors.affiliation: Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Eberstadt
authors.forename: A
authors.initials: A
authors.lastname: Schnuchel
authors.forename: E T
authors.initials: ET
authors.lastname: Olejniczak
authors.forename: R P
authors.initials: RP
authors.lastname: Meadows
authors.forename: J M
authors.initials: JM
authors.lastname: Schkeryantz
authors.forename: D A
authors.initials: DA
authors.lastname: Janowick
authors.forename: J E
authors.initials: JE
authors.lastname: Harlan
authors.forename: E A
authors.initials: EA
authors.lastname: Harris
authors.forename: D E
authors.initials: DE
authors.lastname: Staunton
authors.forename: S W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D001798:Blood Proteins / Q000737:chemistry / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009711:Nucleotides / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D001798:Blood Proteins; D020662:Guanine Nucleotide Exchange Factors; D009711:Nucleotides; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C039077:platelet protein P47; D017346:Protein Serine-Threonine Kinases; C099628:TRIO protein, human