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Heparins mediate the multimer assembly of secreted Noggin

DOI: 10.1002/pro.4419 DOI Help

Authors: Fabian Heide (University of Manitoba) , Scott Legare (University of Manitoba) , Vu To (AbCellera Biologics Inc) , Monika Gupta (University of Manitoba) , Haben Gabir (University of Manitoba) , Thomas Imhof (University of Cologne) , Aniel Moya-Torres (Kisoji Biotechnology Inc) , Matthew Mcdougall (University of Manitoba) , Markus Meier (University of Manitoba) , Manuel Koch (University of Cologne) , Jörg Stetefeld (University of Manitoba)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Protein Science , VOL 31

State: Published (Approved)
Published: September 2022
Diamond Proposal Number(s): 22113

Abstract: Extracellular matrix proteins are most often defined by their direct function that involves receptor binding and subsequent downstream signaling. However, these proteins often contain structural binding regions that allow for the proper localization in the extracellular space which guides its correct function in a local and temporal manner. The regions that serve a structural function, although often associated with disease, tend to have a limited understanding. An example of this is the extracellular matrix protein Noggin; as part of the bone morphogenetic protein inhibitor family, Noggin serves a crucial regulatory function in mammalian developmental stages and later periods of life. Noggin's regular function, after its expression and extracellular release, is mediated by its retention in close proximity to the cellular surface by glycosaminoglycans, specifically heparin and heparan sulfate. Using a biophysical hybrid method approach, we present a close examination of the Noggin heparin binding interface, study its dynamic binding behaviors and observe supramolecular Noggin assemblies mediated by heparin ligands. This confirms previously suggested models of non-covalent protein assemblies mediated through glycosaminoglycans that exist in the extracellular matrix. Further, structural analyses through molecular dynamics simulations allowed us to determine contribution energies for each protein residue involved in ligand binding and correlate this to disease associated mutation data. Our combination of various biophysical and computational methods that characterize the heparin binding interface on Noggin and its protein dynamics expands on the functional understanding of Noggin and can readily be applied to other protein systems.

Journal Keywords: BMP signaling; extracellular matrix organization; heparin binding protein; hybrid method approach; molecular modeling; Noggin; protein multimers

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: B21-High Throughput SAXS

Added On: 22/08/2022 11:01

Discipline Tags:

Biochemistry Chemistry Biophysics Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)