Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence

Abstract The modification of proteins by ubiquitin-fold modifier 1 (UFM1) is implicated in many human diseases. Prior to conjugation, UFM1 undergoes activation by its cognate activating enzyme, UBA5. UBA5 is a non-canonical E1 activating enzyme that possesses an adenylation domain but lacks a distin...

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Autores principales:	Prasanth Padala, Walaa Oweis, Bayan Mashahreh, Nadine Soudah, Einav Cohen-Kfir, Emily A. Todd, Christopher E. Berndsen, Reuven Wiener
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ac087b7b55684d7abb3c727afb7179d7
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spelling	oai:doaj.org-article:ac087b7b55684d7abb3c727afb7179d72021-12-02T16:06:46ZNovel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence10.1038/s41598-017-00610-02045-2322https://doaj.org/article/ac087b7b55684d7abb3c727afb7179d72017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00610-0https://doaj.org/toc/2045-2322Abstract The modification of proteins by ubiquitin-fold modifier 1 (UFM1) is implicated in many human diseases. Prior to conjugation, UFM1 undergoes activation by its cognate activating enzyme, UBA5. UBA5 is a non-canonical E1 activating enzyme that possesses an adenylation domain but lacks a distinct cysteine domain. Binding of UBA5 to UFM1 is mediated via an amino acid sequence, known as the UFM1-interacting sequence (UIS), located outside the adenylation domain that is required for UFM1 activation. However, the precise boundaries of the UIS are yet not clear and are still under debate. Here we revisit the interaction of UFM1 with UBA5 by determining the crystal structure of UFM1 fused to 13 amino acids of human UBA5. Using binding and activity assays, we found that His 336 of UBA5, previously not reported to be part of the UIS, occupies a negatively charged pocket on UFM1’s surface. This His is involved in UFM1 binding and if mutated perturbs activation of UFM1. Surprisingly, we also found that the interaction between two UFM1 molecules mimics how the UIS binds UFM1. Specifically, UFM1 His 70 resembles UBA5 His336 and enters a negatively charged pocked on the other UFM1 molecule. Our results refine our understanding of UFM1-UBA5 binding.Prasanth PadalaWalaa OweisBayan MashahrehNadine SoudahEinav Cohen-KfirEmily A. ToddChristopher E. BerndsenReuven WienerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Prasanth Padala Walaa Oweis Bayan Mashahreh Nadine Soudah Einav Cohen-Kfir Emily A. Todd Christopher E. Berndsen Reuven Wiener Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence
description	Abstract The modification of proteins by ubiquitin-fold modifier 1 (UFM1) is implicated in many human diseases. Prior to conjugation, UFM1 undergoes activation by its cognate activating enzyme, UBA5. UBA5 is a non-canonical E1 activating enzyme that possesses an adenylation domain but lacks a distinct cysteine domain. Binding of UBA5 to UFM1 is mediated via an amino acid sequence, known as the UFM1-interacting sequence (UIS), located outside the adenylation domain that is required for UFM1 activation. However, the precise boundaries of the UIS are yet not clear and are still under debate. Here we revisit the interaction of UFM1 with UBA5 by determining the crystal structure of UFM1 fused to 13 amino acids of human UBA5. Using binding and activity assays, we found that His 336 of UBA5, previously not reported to be part of the UIS, occupies a negatively charged pocket on UFM1’s surface. This His is involved in UFM1 binding and if mutated perturbs activation of UFM1. Surprisingly, we also found that the interaction between two UFM1 molecules mimics how the UIS binds UFM1. Specifically, UFM1 His 70 resembles UBA5 His336 and enters a negatively charged pocked on the other UFM1 molecule. Our results refine our understanding of UFM1-UBA5 binding.
format	article
author	Prasanth Padala Walaa Oweis Bayan Mashahreh Nadine Soudah Einav Cohen-Kfir Emily A. Todd Christopher E. Berndsen Reuven Wiener
author_facet	Prasanth Padala Walaa Oweis Bayan Mashahreh Nadine Soudah Einav Cohen-Kfir Emily A. Todd Christopher E. Berndsen Reuven Wiener
author_sort	Prasanth Padala
title	Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence
title_short	Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence
title_full	Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence
title_fullStr	Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence
title_full_unstemmed	Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence
title_sort	novel insights into the interaction of uba5 with ufm1 via a ufm1-interacting sequence
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ac087b7b55684d7abb3c727afb7179d7
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Novel insights into the interaction of UBA5 with UFM1 via a UFM1-interacting sequence

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