title: Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.
abstract: HtrA2, a trimeric proapoptotic serine protease is involved in several diseases including cancer and neurodegenerative disorders. Its unique ability to mediate apoptosis via multiple pathways makes it an important therapeutic target. In HtrA2, C-terminal PDZ domain upon substrate binding regulates its functions through coordinated conformational changes the mechanism of which is yet to be elucidated. Although allostery has been found in some of its homologs, it has not been characterized in HtrA2 so far. Here, with an in silico and biochemical approach we have shown that allostery does regulate HtrA2 activity. Our studies identified a novel non-canonical selective binding pocket in HtrA2 which initiates signal propagation to the distal active site through a complex allosteric mechanism. This non-classical binding pocket is unique among HtrA family proteins and thus unfolds a novel mechanism of regulation of HtrA2 activity and hence apoptosis.
authors: Advanced Centre for Treatment, Research and Education in Cancer ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, India.
authors: Pruthvi Raj
authors: PR
authors: Bejugam
authors: Raja R
authors: RR
authors: Kuppili
authors: Nitu
authors: N
authors: Singh
authors: Nikhil
authors: N
authors: Gadewal
authors: Lalith K
authors: LK
authors: Chaganti
authors: G Madhavi
authors: GM
authors: Sastry
authors: Kakoli
authors: K
authors: Bose
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D054731:PDZ Domains; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D010455:Peptides; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2