PMID- 32148852
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240212
IS  - 2052-2525 (Print)
IS  - 2052-2525 (Electronic)
IS  - 2052-2525 (Linking)
VI  - 7
IP  - Pt 2
DP  - 2020 Mar 1
TI  - Structural insights into conformational switching in latency-associated peptide 
      between transforming growth factor beta-1 bound and unbound states.
PG  - 238-252
LID - 10.1107/S205225251901707X [doi]
AB  - Transforming growth factor beta-1 (TGFbeta-1) is a secreted signalling protein that 
      directs many cellular processes and is an attractive target for the treatment of 
      several diseases. The primary endogenous activity regulatory mechanism for TGFbeta-1 
      is sequestration by its pro-peptide, latency-associated peptide (LAP), which 
      sterically prohibits receptor binding by caging TGFbeta-1. As such, recombinant LAP 
      is promising as a protein-based therapeutic for modulating TGFbeta-1 activity; 
      however, the mechanism of binding is incompletely understood. Comparison of the 
      crystal structure of unbound LAP (solved here to 3.5 A resolution) with that of 
      the bound complex shows that LAP is in a more open and extended conformation when 
      unbound to TGFbeta-1. Analysis suggests a mechanism of binding TGFbeta-1 through a 
      large-scale conformational change that includes contraction of the inter-monomer 
      interface and caging by the 'straight-jacket' domain that may occur in 
      partnership through a loop-to-helix transition in the core jelly-roll fold. This 
      conformational change does not appear to include a repositioning of the 
      integrin-binding motif as previously proposed. X-ray scattering-based modelling 
      supports this mechanism and reveals possible orientations and ensembles in 
      solution. Although native LAP is heavily glycosylated, solution scattering 
      experiments show that the overall folding and flexibility of unbound LAP are not 
      influenced by glycan modification. The combination of crystallography, solution 
      scattering and biochemical experiments reported here provide insight into the 
      mechanism of LAP sequestration of TGFbeta-1 that is of fundamental importance for 
      therapeutic development.
CI  - (c) Timothy R. Stachowski et al. 2020.
FAU - Stachowski, Timothy R
AU  - Stachowski TR
AUID- ORCID: 0000-0002-6097-4857
AD  - Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 
      14203, USA.
AD  - Cell Stress Biology, Roswell Park Comprehensive Cancer Center, 665 Elm Street, 
      Buffalo, NY 14203, USA.
FAU - Snell, Mary E
AU  - Snell ME
AD  - Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 
      14203, USA.
FAU - Snell, Edward H
AU  - Snell EH
AUID- ORCID: 0000-0001-8714-3191
AD  - Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 
      14203, USA.
AD  - Materials Design and Innovation, State University of New York at Buffalo, 700 
      Ellicott Street, Buffalo, NY 14203, USA.
LA  - eng
GR  - P30 GM124169/GM/NIGMS NIH HHS/United States
GR  - S10 OD018483/OD/NIH HHS/United States
PT  - Journal Article
DEP - 20200206
PL  - England
TA  - IUCrJ
JT  - IUCrJ
JID - 101623101
PMC - PMC7055372
OTO - NOTNLM
OT  - TGFbeta-1
OT  - growth factors
OT  - latency-associated peptide
OT  - structural biology
OT  - transforming growth factor beta-1
EDAT- 2020/03/10 06:00
MHDA- 2020/03/10 06:01
PMCR- 2020/02/06
CRDT- 2020/03/10 06:00
PHST- 2019/09/08 00:00 [received]
PHST- 2019/12/20 00:00 [accepted]
PHST- 2020/03/10 06:00 [entrez]
PHST- 2020/03/10 06:00 [pubmed]
PHST- 2020/03/10 06:01 [medline]
PHST- 2020/02/06 00:00 [pmc-release]
AID - mf5037 [pii]
AID - 10.1107/S205225251901707X [doi]
PST - epublish
SO  - IUCrJ. 2020 Feb 6;7(Pt 2):238-252. doi: 10.1107/S205225251901707X. eCollection 
      2020 Mar 1.