Cargando…

A structural basis for lithium and substrate binding of an inositide phosphatase

Inositol polyphosphate 1-phosphatase (INPP1) is a prototype member of metal-dependent/lithium-inhibited phosphomonoesterase protein family defined by a conserved three-dimensional core structure. Enzymes within this family function in distinct pathways including inositide signaling, gluconeogenesis,...

Descripción completa

Detalles Bibliográficos
Autores principales: Dollins, D. Eric, Xiong, Jian-Ping, Endo-Streeter, Stuart, Anderson, David E., Bansal, Vinay S., Ponder, Jay W., Ren, Yi, York, John D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948987/
https://www.ncbi.nlm.nih.gov/pubmed/33172890
http://dx.doi.org/10.1074/jbc.RA120.014057
_version_ 1783663469821689856
author Dollins, D. Eric
Xiong, Jian-Ping
Endo-Streeter, Stuart
Anderson, David E.
Bansal, Vinay S.
Ponder, Jay W.
Ren, Yi
York, John D.
author_facet Dollins, D. Eric
Xiong, Jian-Ping
Endo-Streeter, Stuart
Anderson, David E.
Bansal, Vinay S.
Ponder, Jay W.
Ren, Yi
York, John D.
author_sort Dollins, D. Eric
collection PubMed
description Inositol polyphosphate 1-phosphatase (INPP1) is a prototype member of metal-dependent/lithium-inhibited phosphomonoesterase protein family defined by a conserved three-dimensional core structure. Enzymes within this family function in distinct pathways including inositide signaling, gluconeogenesis, and sulfur assimilation. Using structural and biochemical studies, we report the effect of substrate and lithium on a network of metal binding sites within the catalytic center of INPP1. We find that lithium preferentially occupies a key site involved in metal-activation only when substrate or product is added. Mutation of a conserved residue that selectively coordinates the putative lithium-binding site results in a dramatic 100-fold reduction in the inhibitory constant as compared with wild-type. Furthermore, we report the INPP1/inositol 1,4-bisphosphate complex which illuminates key features of the enzyme active site. Our results provide insights into a structural basis for uncompetitive lithium inhibition and substrate recognition and define a sequence motif for metal binding within this family of regulatory phosphatases.
format Online
Article
Text
id pubmed-7948987
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher American Society for Biochemistry and Molecular Biology
record_format MEDLINE/PubMed
spelling pubmed-79489872021-03-19 A structural basis for lithium and substrate binding of an inositide phosphatase Dollins, D. Eric Xiong, Jian-Ping Endo-Streeter, Stuart Anderson, David E. Bansal, Vinay S. Ponder, Jay W. Ren, Yi York, John D. J Biol Chem Research Article Inositol polyphosphate 1-phosphatase (INPP1) is a prototype member of metal-dependent/lithium-inhibited phosphomonoesterase protein family defined by a conserved three-dimensional core structure. Enzymes within this family function in distinct pathways including inositide signaling, gluconeogenesis, and sulfur assimilation. Using structural and biochemical studies, we report the effect of substrate and lithium on a network of metal binding sites within the catalytic center of INPP1. We find that lithium preferentially occupies a key site involved in metal-activation only when substrate or product is added. Mutation of a conserved residue that selectively coordinates the putative lithium-binding site results in a dramatic 100-fold reduction in the inhibitory constant as compared with wild-type. Furthermore, we report the INPP1/inositol 1,4-bisphosphate complex which illuminates key features of the enzyme active site. Our results provide insights into a structural basis for uncompetitive lithium inhibition and substrate recognition and define a sequence motif for metal binding within this family of regulatory phosphatases. American Society for Biochemistry and Molecular Biology 2020-11-24 /pmc/articles/PMC7948987/ /pubmed/33172890 http://dx.doi.org/10.1074/jbc.RA120.014057 Text en © 2020 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Dollins, D. Eric
Xiong, Jian-Ping
Endo-Streeter, Stuart
Anderson, David E.
Bansal, Vinay S.
Ponder, Jay W.
Ren, Yi
York, John D.
A structural basis for lithium and substrate binding of an inositide phosphatase
title A structural basis for lithium and substrate binding of an inositide phosphatase
title_full A structural basis for lithium and substrate binding of an inositide phosphatase
title_fullStr A structural basis for lithium and substrate binding of an inositide phosphatase
title_full_unstemmed A structural basis for lithium and substrate binding of an inositide phosphatase
title_short A structural basis for lithium and substrate binding of an inositide phosphatase
title_sort structural basis for lithium and substrate binding of an inositide phosphatase
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948987/
https://www.ncbi.nlm.nih.gov/pubmed/33172890
http://dx.doi.org/10.1074/jbc.RA120.014057
work_keys_str_mv AT dollinsderic astructuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT xiongjianping astructuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT endostreeterstuart astructuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT andersondavide astructuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT bansalvinays astructuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT ponderjayw astructuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT renyi astructuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT yorkjohnd astructuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT dollinsderic structuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT xiongjianping structuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT endostreeterstuart structuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT andersondavide structuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT bansalvinays structuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT ponderjayw structuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT renyi structuralbasisforlithiumandsubstratebindingofaninositidephosphatase
AT yorkjohnd structuralbasisforlithiumandsubstratebindingofaninositidephosphatase