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SMALLOSTERY SIGNED

Single-molecule spectroscopy of coordinated motions in allosteric proteins

Total Cost €

EC-Contrib. €

Partnership

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SMALLOSTERY project word cloud

Explore the words cloud of the SMALLOSTERY project. It provides you a very rough idea of what is the project "SMALLOSTERY" about.

concerted proteins disaggregating exploring clpb family single protein experimental drugs subunits function time conformational effector rely attained broken catalogue methodology site symmetry dynamics homo coordinated allosteric regulation relative carefully follow basis deficiency simultaneously rxr synchronization units labels representing critical transmission transition scenario propagation heterodimers distances structural molecule dynamic contributes framework groel binding multiple conserves model domains spectroscopy ordered explore ameliorating oligomeric transitions fret communication dependent folder effect molecules probing efforts fundamental sequential allostery ligands poorly machine entails dna motions contain dramatically first spread influencing

Project "SMALLOSTERY" data sheet

The following table provides information about the project.

Coordinator	WEIZMANN INSTITUTE OF SCIENCE Organization address address: HERZL STREET 234 city: REHOVOT postcode: 7610001 website: www.weizmann.ac.il contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.
Coordinator Country	Israel [IL]
Total cost	2˙484˙722 €
EC max contribution	2˙484˙722 € (100%)
Programme	1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
Code Call	ERC-2016-ADG
Funding Scheme	ERC-ADG
Starting year	2017
Duration (year-month-day)	from 2017-05-01 to 2022-04-30

Partnership

Take a look of project's partnership.

#	participants	country	role	EC contrib. [€]
1	WEIZMANN INSTITUTE OF SCIENCE WEIZMANN INSTITUTE OF SCIENCE Organization address address: HERZL STREET 234 city: REHOVOT postcode: 7610001 website: www.weizmann.ac.il contact info title: n.a. name: n.a. surname: n.a. function: n.a. email: n.a. telephone: n.a. fax: n.a.	IL (REHOVOT)	coordinator	2˙484˙722.00

Map

Project objective

Critical for the function of many proteins, allosteric communication involves transmission of the effect of binding at one site of a protein to another through conformational changes. Yet the structural and dynamic basis for allostery remains poorly understood. In particular, there is no method to follow coordinated large-scale motions of domains and subunits in proteins as they occur. Since the subunits of allosteric proteins often contain multiple domains, any such method entails probing the dynamics along several intra-protein distances simultaneously. This proposal aims at ameliorating this deficiency by creating the experimental framework for exploring time-dependent coordination of allosteric transitions of multiple units within proteins. Our methodology will rely on single-molecule FRET spectroscopy with multiple labels on the same protein and advanced analysis. We will explore fundamental issues in protein dynamics: relative motions of domains within subunits, propagation of conformational change between subunits, and synchronization of these motions by effector molecules. To investigate these issues, we have carefully selected three model systems, each representing an important scenario of allosteric regulation. While the homo-oligomeric protein-folder GroEL conserves symmetry in a concerted transition between major structural states, the symmetry of the homo-oligomeric disaggregating machine ClpB is broken via a sequential transition. Symmetry is attained only after binding to DNA and ligands in the third system, the family of RXR heterodimers. This exciting project will provide the very first catalogue of coordinated and time-ordered motions within and between subunits of allosteric proteins and the first measurement of the time scale of the conformational spread through a large protein. It will enhance dramatically our understanding of how allostery contributes to protein function, influencing future efforts to design drugs for allosteric proteins.

Publications

List of publications.
year	authors and title	journal	last update
2019	Hisham Mazal, Gilad Haran Single-molecule FRET methods to study the dynamics of proteins at work published pages: 8-17, ISSN: 2468-4511, DOI: 10.1016/j.cobme.2019.08.007	Current Opinion in Biomedical Engineering 12	2020-02-06
2019	Hisham Mazal, Marija Iljina, Yoav Barak, Nadav Elad, Rina Rosenzweig, Pierre Goloubinoff, Inbal Riven, Gilad Haran Tunable microsecond dynamics of an allosteric switch regulate the activity of a AAA+ disaggregation machine published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-019-09474-6	Nature Communications 10/1	2020-01-29
2018	Haim Yuval Aviram, Menahem Pirchi, Hisham Mazal, Yoav Barak, Inbal Riven, Gilad Haran Direct observation of ultrafast large-scale dynamics of an enzyme under turnover conditions published pages: 3243-3248, ISSN: 0027-8424, DOI: 10.1073/pnas.1720448115	Proceedings of the National Academy of Sciences 115/13	2019-10-08

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