Universität zu Köln

Heide, Fabian ORCID: 0000-0002-6849-3177, Legare, Scott, To, Vu, Gupta, Monika, Gabir, Haben, Imhof, Thomas, Moya-Torres, Aniel ORCID: 0000-0001-7935-2591, McDougall, Matthew, Meier, Markus ORCID: 0000-0003-1068-746X, Koch, Manuel ORCID: 0000-0002-2962-7814 and Stetefeld, Jorg (2022). Heparins mediate the multimer assembly of secreted Noggin. Protein Sci., 31 (9). HOBOKEN: WILEY. ISSN 1469-896X

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Heide, Fabian UNSPECIFIED orcid.org/0000-0002-6849-3177 UNSPECIFIED Legare, Scott UNSPECIFIED UNSPECIFIED UNSPECIFIED To, Vu UNSPECIFIED UNSPECIFIED UNSPECIFIED Gupta, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Gabir, Haben UNSPECIFIED UNSPECIFIED UNSPECIFIED Imhof, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Moya-Torres, Aniel UNSPECIFIED orcid.org/0000-0001-7935-2591 UNSPECIFIED McDougall, Matthew UNSPECIFIED UNSPECIFIED UNSPECIFIED Meier, Markus UNSPECIFIED orcid.org/0000-0003-1068-746X UNSPECIFIED Koch, Manuel UNSPECIFIED orcid.org/0000-0002-2962-7814 UNSPECIFIED Stetefeld, Jorg UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-671601
DOI:	10.1002/pro.4419
Journal or Publication Title:	Protein Sci.
Volume:	31
Number:	9
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1469-896X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SMALL-ANGLE SCATTERING; PROXIMAL SYMPHALANGISM; CELL-SURFACE; SULFATE; PROTEOGLYCANS; GROWTH; ANTAGONISM; EXPRESSION; MUTATIONS; MECHANISM Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67160