Molecular model of the G protein. alpha. subunit based on the crystal structure of the HRAS protein

Journal Article · Wed Mar 01 00:00:00 EST 1989 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.86.6.1751· OSTI ID:5085877

Holbrook, S R; Kim, Sunghou ^[1]

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1. Lawrence Berkeley Laboratory, CA (USA)

A structural model of guanine nucleotide-binding regulatory protein {alpha} subunits (G{sub {alpha}} subunits) is proposed based on the crystal structure of the catalytic domain of the human HRAS protein (p21{sup ras}). Because of low overall sequence similarity, structural and functional constraints were used to align the G{sub {alpha}} consensus sequence with that of p21{sup ras}. The resulting G{sub {alpha}} model specifies the spatial relationship among the guanine nucleotide-binding site, the binding site of the {beta}{gamma} subunit complex, likely regions of effector and receptor interaction, and sites of cholera and pertussis toxin modification. The locations in the model of the experimentally determined sites of proteolytic digestion, point mutation, monoclonal antibody binding, and toxin modification are consistent with and help explain the observed biological activity. Two important findings from our model are (i) the orientation of the G{sub {alpha}} model with respect to the membrane and (ii) the identification of the spatial proximity of the N- and C-terminal regions. Furthermore, by analogy to p21{sup ras}, the model assigns specific residues in G{sub {alpha}} required for binding the guanosine (G-box) and phosphates (PO{sub 4}-box) and identifies residues potentially involved in the conformational switch mechanism (S-box). Specification of these critical regions in the G{sub {alpha}} model suggests guidelines for construction of mutants and chimeric proteins to experimentally test structural and functional hypotheses.

• DOE Contract Number: AC03-76SF00098
• OSTI ID: 5085877
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Vol. 86:6; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
PROTEINS
MOLECULAR MODELS
AMINO ACID SEQUENCE
CELL MEMBRANES
GENE MUTATIONS
GUANINE
GUANOSINE
AMINES
AROMATICS
AZAARENES
CELL CONSTITUENTS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
MATHEMATICAL MODELS
MEMBRANES
MOLECULAR STRUCTURE
MUTATIONS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PURINES
RIBOSIDES
550200* - Biochemistry