Evidence map›Paper›PMID 36801015›Full record

ArticleCell systems2023

A complete allosteric map of a GTPase switch in its native cellular network.

Christopher J P Mathy, Parul Mishra, Julia M Flynn, Tina Perica, David Mavor, Daniel N A Bolon, Tanja Kortemme

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell systems, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.

0numbers the graph read from it
0cells of the map it votes in
17citing papers in PubMed
2.9field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

17 citing papers in PubMed, 19 citations in OpenAlex.

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  15. Emerging maps of allosteric regulation in cellular networks.Current opinion in structural biology · 2023
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 2 institutions in 2 countries.

Christopher J P MathyDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA; The UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA.
Parul MishraDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, MA 01605, USA; School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.
Julia M FlynnDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Tina PericaDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
David MavorDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Daniel N A BolonDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: dan.bolon@umassmed.edu.
Tanja KortemmeDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94158, USA; The UC Berkeley-UCSF Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: tanjakortemme@gmail.com.
University of Massachusetts Chan Medical School · USQB3 · US

Funding

Equipment Supplement - Computational design of proteins and protein functionsR35GM145236 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KORTEMME, TANJA · 2022 to 2025
$2.4M
Discovery of Protein Network FunctionR01GM117189 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KORTEMME, TANJA · 2016 to 2019
$2.2M
NIGMS NIH HHS R01 GM117189NIGMS NIH HHS R35 GM145236
6 · The paper itself

Abstract

Allosteric regulation is central to protein function in cellular networks. A fundamental open question is whether cellular regulation of allosteric proteins occurs only at a few defined positions or at many sites distributed throughout the structure. Here, we probe the regulation of GTPases-protein switches that control signaling through regulated conformational cycling-at residue-level resolution by deep mutagenesis in the native biological network. For the GTPase Gsp1/Ran, we find that 28% of the 4,315 assayed mutations show pronounced gain-of-function responses. Twenty of the sixty positions enriched for gain-of-function mutations are outside the canonical GTPase active site switch regions. Kinetic analysis shows that these distal sites are allosterically coupled to the active site. We conclude that the GTPase switch mechanism is broadly sensitive to cellular allosteric regulation. Our systematic discovery of new regulatory sites provides a functional map to interrogate and target GTPases controlling many essential biological processes.

Indexed as

GTP PhosphohydrolasesProteinsAllosteric RegulationAllosteric SiteKineticsGTP PhosphohydrolasesProteinsallosterycellular regulationGsp1GTPasesmutational scanningprotein networksRan

Identifiers

PMID36801015
PMCPMC10173951
OpenAlexW4321208420

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.