title: Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly.
abstract: The assembly of the tropoelastin monomer into elastin is vital for conferring elasticity on blood vessels, skin, and lungs. Tropoelastin has dual needs for flexibility and structure in self-assembly. We explore the structure-dynamics-function interplay, consider the duality of molecular order and disorder, and identify equally significant functional contributions by local and global structures. To study these organizational stratifications, we perturb a key hinge region by expressing an exon that is universally spliced out in human tropoelastins. We find a herniated nanostructure with a displaced C terminus and explain by molecular modeling that flexible helices are replaced with substantial β sheets. We see atypical higher-order cross-linking and inefficient assembly into discontinuous, thick elastic fibers. We explain this dysfunction by correlating local and global structural effects with changes in the molecule's assembly dynamics. This work has general implications for our understanding of elastomeric proteins, which balance disordered regions with defined structural modules at multiple scales for functional assembly.
authors.affiliation: Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales 2006, Australia.; School of Molecular Bioscience, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Giselle C
authors.initials: GC
authors.lastname: Yeo
authors.affiliation: Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Tarakanova
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Clair
authors.initials: C
authors.lastname: Baldock
authors.affiliation: The Heart Research Institute, Newtown, New South Wales 2050, Australia.
authors.forename: Steven G
authors.identifier: 0000-0001-7964-819X
authors.initials: SG
authors.lastname: Wise
authors.affiliation: Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Buehler
authors.affiliation: Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales 2006, Australia.; School of Molecular Bioscience, The University of Sydney, Sydney, New South Wales 2006, Australia.; Bosch Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Anthony S
authors.identifier: 0000-0002-8106-4836
authors.initials: AS
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D019245:Compressive Strength; D004547:Elastic Tissue / Q000737:chemistry; D004548:Elasticity; D004549:Elastin / Q000737:chemistry; D005091:Exons; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D049329:Nanostructures / Q000737:chemistry; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014333:Tropoelastin / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D055114:X-Ray Microtomography
chemical_list: D020100:Hydrogels; D014333:Tropoelastin; D004549:Elastin
keywords: Tropoelastin; connective tissue; modeling