Structural insights into conformational switching in latency-associated peptide between transforming growth factor β-1 bound and unbound states

IUCrJ
Timothy StachowskiEdward H Snell

Abstract

Transforming growth factor β-1 (TGFβ-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 TGFβ-1 is sequestration by its pro-peptide, latency-associated peptide (LAP), which sterically prohibits receptor binding by caging TGFβ-1. As such, recombinant LAP is promising as a protein-based therapeutic for modulating TGFβ-1 activity; however, the mechanism of binding is incompletely understood. Comparison of the crystal structure of unbound LAP (solved here to 3.5 Å resolution) with that of the bound complex shows that LAP is in a more open and extended conformation when unbound to TGFβ-1. Analysis suggests a mechanism of binding TGFβ-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 ensemb...Continue Reading

References

Mar 9, 1989·Nature·K Miyazono, C H Heldin
Apr 28, 1968·Journal of Molecular Biology·B W Matthews
Jan 1, 1981·Advances in Protein Chemistry·J S Richardson
Mar 31, 1995·The Journal of Biological Chemistry·S Schultz-CherryJ E Murphy-Ullrich
Jun 11, 1996·Proceedings of the National Academy of Sciences of the United States of America·E P BöttingerM B Sporn
Feb 15, 1996·Structure·T StehleS C Harrison
Oct 26, 1999·Acta Crystallographica. Section D, Biological Crystallography·H R Powell
Apr 30, 2003·Journal of Structural Biology·Joseph R LuftGeorge T DeTitta
Jul 5, 2003·The Journal of Clinical Endocrinology and Metabolism·Signe PerlmanHans T Schambye
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Nov 18, 2005·Cytokine & Growth Factor Reviews·Brian Bierie, Harold L Moses
Feb 14, 2006·Trends in Biochemical Sciences·Nivedita MitraAvadhesha Surolia
Oct 13, 2006·Nature Biotechnology·Gary Walsh, Roy Jefferis
Dec 8, 2006·Radiation Research·Michael F JoblingMary Helen Barcellos-Hoff
Aug 31, 2007·Biologicals : Journal of the International Association of Biological Standardization·Rodney KeckAndrew Jones
Dec 21, 2007·Acta Crystallographica. Section D, Biological Crystallography·Thomas C TerwilligerPaul D Adams
Mar 18, 2009·Developmental Cell·Mary Y Wu, Caroline S Hill
Jul 18, 2009·Carbohydrate Research·David RussellBenjamin G Davis
Sep 3, 2009·Journal of Structural Biology·Dominique DurandFranck Fieschi
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·T Geoff G BattyeAndrew G W Leslie
Jun 17, 2011·Nature·Minlong ShiTimothy A Springer
Jul 12, 2011·Structure·Reza Khayat, John E Johnson
Jul 29, 2011·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Chao YuSimon J Davis
Oct 4, 2011·Journal of Structural Biology·Zheng YangThomas E Ferrin
Sep 25, 2012·Nature Reviews. Drug Discovery·Rosemary J Akhurst, Akiko Hata
Nov 13, 2012·Current Opinion in Structural Biology·WeiShen AikChristopher J Schofield
Apr 27, 2013·Nature·Robert P Rambo, John A Tainer
May 25, 2013·Journal of Molecular Biology·René BagerPeter A Andreasen
Jun 26, 2013·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans, Garib N Murshudov
Jun 27, 2013·Wiley Interdisciplinary Reviews. Developmental Biology·Alexander Weiss, Liliana Attisano

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Methods Mentioned

BETA
glycosylation
protein folding
PCR
size-exclusion chromatography
transfection
ELISA
X-ray
circular-dichroism
NMR

Software Mentioned

UCSF Chimera
CRYSOL
GNOM
RAW
ROSETTA
AIMLESS
CorMap
GAJOE
MODELLER
PyMOL

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