Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells

Abstract Noonan syndrome (NS) is a congenital hereditary disorder associated with developmental and cardiac defects. Some patients with NS carry mutations in SOS, a guanine nucleotide exchange factor (GEF) for the small GTPase RAS. NS mutations have been identified not only in the GEF domain, but al...

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Autores principales:	Yuki Nakamura, Nobuhisa Umeki, Mitsuhiro Abe, Yasushi Sako
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/62082c7d410c48a7ab7fd1d3789c1708
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spelling	oai:doaj.org-article:62082c7d410c48a7ab7fd1d3789c17082021-12-02T15:05:52ZMutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells10.1038/s41598-017-14190-62045-2322https://doaj.org/article/62082c7d410c48a7ab7fd1d3789c17082017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-14190-6https://doaj.org/toc/2045-2322Abstract Noonan syndrome (NS) is a congenital hereditary disorder associated with developmental and cardiac defects. Some patients with NS carry mutations in SOS, a guanine nucleotide exchange factor (GEF) for the small GTPase RAS. NS mutations have been identified not only in the GEF domain, but also in various domains of SOS, suggesting that multiple mechanisms disrupt SOS function. In this study, we examined three NS mutations in different domains of SOS to clarify the abnormality in its translocation to the plasma membrane, where SOS activates RAS. The association and dissociation kinetics between SOS tagged with a fluorescent protein and the living cell surface were observed in single molecules. All three mutants showed increased affinity for the plasma membrane, inducing excessive RAS signalling. However, the mechanisms by which their affinity was increased were specific to each mutant. Conformational disorder in the resting state, increased probability of a conformational change on the plasma membrane, and an increased association rate constant with the membrane receptor are the suggested mechanisms. These different properties cause the specific phenotypes of the mutants, which should be rescuable with different therapeutic strategies. Therefore, single-molecule kinetic analyses of living cells are useful for the pathological analysis of genetic diseases.Yuki NakamuraNobuhisa UmekiMitsuhiro AbeYasushi SakoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuki Nakamura Nobuhisa Umeki Mitsuhiro Abe Yasushi Sako Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells
description	Abstract Noonan syndrome (NS) is a congenital hereditary disorder associated with developmental and cardiac defects. Some patients with NS carry mutations in SOS, a guanine nucleotide exchange factor (GEF) for the small GTPase RAS. NS mutations have been identified not only in the GEF domain, but also in various domains of SOS, suggesting that multiple mechanisms disrupt SOS function. In this study, we examined three NS mutations in different domains of SOS to clarify the abnormality in its translocation to the plasma membrane, where SOS activates RAS. The association and dissociation kinetics between SOS tagged with a fluorescent protein and the living cell surface were observed in single molecules. All three mutants showed increased affinity for the plasma membrane, inducing excessive RAS signalling. However, the mechanisms by which their affinity was increased were specific to each mutant. Conformational disorder in the resting state, increased probability of a conformational change on the plasma membrane, and an increased association rate constant with the membrane receptor are the suggested mechanisms. These different properties cause the specific phenotypes of the mutants, which should be rescuable with different therapeutic strategies. Therefore, single-molecule kinetic analyses of living cells are useful for the pathological analysis of genetic diseases.
format	article
author	Yuki Nakamura Nobuhisa Umeki Mitsuhiro Abe Yasushi Sako
author_facet	Yuki Nakamura Nobuhisa Umeki Mitsuhiro Abe Yasushi Sako
author_sort	Yuki Nakamura
title	Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells
title_short	Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells
title_full	Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells
title_fullStr	Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells
title_full_unstemmed	Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells
title_sort	mutation-specific mechanisms of hyperactivation of noonan syndrome sos molecules detected with single-molecule imaging in living cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/62082c7d410c48a7ab7fd1d3789c1708
work_keys_str_mv	AT yukinakamura mutationspecificmechanismsofhyperactivationofnoonansyndromesosmoleculesdetectedwithsinglemoleculeimaginginlivingcells AT nobuhisaumeki mutationspecificmechanismsofhyperactivationofnoonansyndromesosmoleculesdetectedwithsinglemoleculeimaginginlivingcells AT mitsuhiroabe mutationspecificmechanismsofhyperactivationofnoonansyndromesosmoleculesdetectedwithsinglemoleculeimaginginlivingcells AT yasushisako mutationspecificmechanismsofhyperactivationofnoonansyndromesosmoleculesdetectedwithsinglemoleculeimaginginlivingcells
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Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells

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