Evidence map›Paper›PMID 31968260›Full record

ArticleCell reports2020

Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants.

Gabriel Velez, Young Joo Sun, Saif Khan, Jing Yang, Jonathan Herrmann, Teja Chemudupati, Robert E MacLaren, Lokesh Gakhar, Soichi Wakatsuki, Alexander G Bassuk and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
–field-weighted citation impact
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

12 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Hippocampal mitochondrial CaSaudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023
    Article
  5. Article
  6. Review
  7. Article
  8. Review
  9. The C2 domain of calpain 5 contributes to enzyme activation and membrane localization.Biochimica et biophysica acta. Molecular cell research · 2021
    Article
  10. Article
  11. Article
  12. Review
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

11 authors.

Gabriel VelezOmics Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA; Medical Scientist Training Program, University of Iowa, Iowa City, IA 52242, USA.
Young Joo SunOmics Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
Saif KhanProtein and Crystallography Facility, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA; Department of Biology and Biochemistry, University of Bath, Bath BA2 7AX, UK.
Jing YangOmics Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
Jonathan HerrmannDepartment of Structural Biology, Stanford University, Palo Alto, CA 94305, USA; Photon Science, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
Teja ChemudupatiOmics Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.
Robert E MacLarenNIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford EC1V 2PD, UK; Oxford Eye Hospital, University of Oxford NHS Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Lokesh GakharProtein and Crystallography Facility, University of Iowa, Iowa City, IA 52242, USA; Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Soichi WakatsukiDepartment of Structural Biology, Stanford University, Palo Alto, CA 94305, USA; Photon Science, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
Alexander G BassukDepartment of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
Vinit B MahajanOmics Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address: vinit.mahajan@stanford.edu.

Funding

X-ray Absorption Spectroscopy (XAS) pp.711-759P41GM103393 · NIGMS · STANFORD UNIVERSITY · PI HODGSON, KEITH O · 2012 to 2019
$30.6M
MEDICAL SCIENTIST TRAINING PROGRAMT32GM007337 · NIGMS · UNIVERSITY OF IOWA · PI GEYER, PAMELA K., LENTZ, STEVEN R · 1985 to 2020
$15.9M
Stanford Vision Research CoreP30EY026877 · NEI · STANFORD UNIVERSITY · PI STEPHEN A BACCUS · 2017 to 2026
$8.0M
Gene Silencing and Gene Editing in PhototransductionR01EY024698 · NEI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Stephen H Tsang · 2015 to 2026
$4.7M
Structure and Function of Calpain-5R01EY024665 · NEI · UNIVERSITY OF IOWA · PI MAHAJAN, VINIT B · 2015 to 2019
$1.9M
Development of a novel treatment for hyperbilirubinemia-induced kernicterusR01HD084422 · NICHD · STANFORD UNIVERSITY · PI MOCHLY-ROSEN, DARIA, STEVENSON, DAVID K · 2016 to 2020
$1.6M
Mechanistic Studies on Regenerative Medicine Approaches to Childhood BlindnessR01EY026682 · NEI · UNIVERSITY OF IOWA · PI BASSUK, ALEXANDER G, MAHAJAN, VINIT B · 2016 to 2019
$1.6M
Mechanism-based therapies for photoreceptor degenerationR01EY025225 · NEI · UNIVERSITY OF IOWA · PI MAHAJAN, VINIT B · 2015 to 2018
$1.3M
Evaluating GWAS AMD Candidate Loci by Gene Editing in Human iPS CellsR21AG050437 · NIA · UNIVERSITY OF IOWA · PI BASSUK, ALEXANDER G, MAHAJAN, VINIT B · 2015 to 2016
$431k
Structure-function studies of Calpain-5 in hereditary uveitisF30EY027986 · NEI · UNIVERSITY OF IOWA · PI VELEZ, GABRIEL · 2018 to 2021
$164k
NEI NIH HHS F30 EY027986NEI NIH HHS P30 EY026877NEI NIH HHS R01 EY024665NEI NIH HHS R01 EY024698NEI NIH HHS R01 EY025225NEI NIH HHS R01 EY026682NIA NIH HHS R21 AG050437NICHD NIH HHS R01 HD084422NIGMS NIH HHS P41 GM103393NIGMS NIH HHS T32 GM007337
6 · The paper itself

Abstract

Increased calpain activity is linked to neuroinflammation including a heritable retinal disease caused by hyper-activating mutations in the calcium-activated calpain-5 (CAPN5) protease. Although structures for classical calpains are known, the structure of CAPN5, a non-classical calpain, remains undetermined. Here we report the 2.8 Å crystal structure of the human CAPN5 protease core (CAPN5-PC). Compared to classical calpains, CAPN5-PC requires high calcium concentrations for maximal activity. Structure-based phylogenetic analysis and multiple sequence alignment reveal that CAPN5-PC contains three elongated flexible loops compared to its classical counterparts. The presence of a disease-causing mutation (c.799G>A, p.Gly267Ser) on the unique PC2L2 loop reveals a function in this region for regulating enzymatic activity. This mechanism could be transferred to distant calpains, using synthetic calpain hybrids, suggesting an evolutionary mechanism for fine-tuning calpain function by modifying flexible loops. Further, the open (inactive) conformation of CAPN5-PC provides structural insight into CAPN5-specific residues that can guide inhibitor design.

Indexed as

Amino Acid SequenceCalciumCalpainConserved SequenceCrystallography, X-RayDiseaseEnzyme ActivationEvolution, MolecularHumansMutationPhylogenyProtein DomainsCalciumCalpainCapn5 protein, humancalcium-binding proteincalpainCAPN5crystal structuredisease-causing mutationsenzyme kineticsNIVproteasestructural phylogeneticssynthetic biologyuveitis

Identifiers

PMID31968260
PMCPMC7001764

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Registered trials

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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.