title: Oncogenic mutations reduce the stability of SRC kinase.
abstract: The oncogenic potential of the viral tyrosine kinase v-Src is due to its constitutive activity. Unlike the highly homologous cellular c-Src kinase, a C-terminal deletion of the regulatory tail and numerous point mutations make the viral kinase uncontrollable. To determine the basis of these differences, we analysed the structure and stability of v-Src and c-Src in vitro. We show that the stability of v-Src against unfolding and irreversible aggregation is significantly lower than that of c-Src. Furthermore, in v-Src hydrophobic residues are more exposed already in the native state. In consequence, v-Src was found to be inactive close to physiological temperatures. We thus suggest that the ensemble of mutations that transform c-Src into the oncogenic variant cause a concomitant destabilisation of the kinase.
authors.affiliation: Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: S Fabio
authors.initials: SF
authors.lastname: Falsone
authors.forename: Sebastian
authors.initials: S
authors.lastname: Leptihn
authors.forename: Anja
authors.initials: A
authors.lastname: Osterauer
authors.forename: Martin
authors.initials: M
authors.lastname: Haslbeck
authors.forename: Johannes
authors.initials: J
authors.lastname: Buchner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D000081247:CSK Tyrosine-Protein Kinase; D002645:Chickens; D018076:DNA, Complementary / Q000235:genetics; D004795:Enzyme Stability; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015688:Oncogene Protein pp60(v-src) / Q000737:chemistry / Q000235:genetics; D010766:Phosphorylation; D011489:Protein Denaturation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D019061:src-Family Kinases / Q000737:chemistry* / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D015688:Oncogene Protein pp60(v-src); D019061:src-Family Kinases