Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.

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 it...

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Autores principales:	Pruthvi Raj Bejugam, Raja R Kuppili, Nitu Singh, Nikhil Gadewal, Lalith K Chaganti, G Madhavi Sastry, Kakoli Bose
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a082cf1738d54a3ebf60f793d87e6eb6
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spelling	oai:doaj.org-article:a082cf1738d54a3ebf60f793d87e6eb62021-11-18T07:57:32ZAllosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.1932-620310.1371/journal.pone.0055416https://doaj.org/article/a082cf1738d54a3ebf60f793d87e6eb62013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23457469/?tool=EBIhttps://doaj.org/toc/1932-6203HtrA2, 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.Pruthvi Raj BejugamRaja R KuppiliNitu SinghNikhil GadewalLalith K ChagantiG Madhavi SastryKakoli BosePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 2, p e55416 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pruthvi Raj Bejugam Raja R Kuppili Nitu Singh Nikhil Gadewal Lalith K Chaganti G Madhavi Sastry Kakoli Bose Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.
description	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.
format	article
author	Pruthvi Raj Bejugam Raja R Kuppili Nitu Singh Nikhil Gadewal Lalith K Chaganti G Madhavi Sastry Kakoli Bose
author_facet	Pruthvi Raj Bejugam Raja R Kuppili Nitu Singh Nikhil Gadewal Lalith K Chaganti G Madhavi Sastry Kakoli Bose
author_sort	Pruthvi Raj Bejugam
title	Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.
title_short	Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.
title_full	Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.
title_fullStr	Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.
title_full_unstemmed	Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.
title_sort	allosteric regulation of serine protease htra2 through novel non-canonical substrate binding pocket.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/a082cf1738d54a3ebf60f793d87e6eb6
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Allosteric regulation of serine protease HtrA2 through novel non-canonical substrate binding pocket.

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