3UTO

Twitchin kinase region from C.elegans (Fn31-NL-kin-CRD-Ig26)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Identification of an N-terminal inhibitory extension as the primary mechanosensory regulator of twitchin kinase.

von Castelmur, E.Strumpfer, J.Franke, B.Bogomolovas, J.Barbieri, S.Qadota, H.Konarev, P.V.Svergun, D.I.Labeit, S.Benian, G.M.Schulten, K.Mayans, O.

(2012) Proc Natl Acad Sci U S A 109: 13608-13613

  • DOI: https://doi.org/10.1073/pnas.1200697109
  • Primary Citation of Related Structures:  
    3UTO

  • PubMed Abstract: 

    Titin-like kinases are an important class of cytoskeletal kinases that intervene in the response of muscle to mechanical stimulation, being central to myofibril homeostasis and development. These kinases exist in autoinhibited states and, allegedly, become activated during muscle activity by the elastic unfolding of a C-terminal regulatory segment (CRD). However, this mechano-activation model remains controversial. Here we explore the structural, catalytic, and tensile properties of the multidomain kinase region of Caenorhabditis elegans twitchin (Fn(31)-Nlinker-kinase-CRD-Ig(26)) using X-ray crystallography, small angle X-ray scattering, molecular dynamics simulations, and catalytic assays. This work uncovers the existence of an inhibitory segment that flanks the kinase N-terminally (N-linker) and that acts synergistically with the canonical CRD tail to silence catalysis. The N-linker region has high mechanical lability and acts as the primary stretch-sensor in twitchin kinase, while the CRD is poorly responsive to pulling forces. This poor response suggests that the CRD is not a generic mechanosensor in this kinase family. Instead, the CRD is shown here to be permissive to catalysis and might protect the kinase active site against mechanical damage. Thus, we put forward a regulatory model where kinase inhibition results from the combined action of both N- and C-terminal tails, but only the N-terminal extension undergoes mechanical removal, thereby affording partial activation. Further, we compare invertebrate and vertebrate titin-like kinases and identify variations in the regulatory segments that suggest a mechanical speciation of these kinase classes.


  • Organizational Affiliation

    Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Twitchin
A, B
573Caenorhabditis elegansMutation(s): 0 
Gene Names: unc-22ZK617.1
EC: 2.7.11.1
UniProt
Find proteins for Q23551 (Caenorhabditis elegans)
Explore Q23551 
Go to UniProtKB:  Q23551
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ23551
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.176 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.7α = 90
b = 158.21β = 90
c = 60.46γ = 90
Software Package:
Software NamePurpose
DNAdata collection
PHASERphasing
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-08-08
    Type: Initial release
  • Version 1.1: 2012-09-12
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations, Structure summary