Direct Visualization of the Binding of Transforming Growth Factor Beta 1 with Cartilage Oligomeric Matrix Protein via High-Resolution Atomic Force Microscopy

Victoria Tran, Arpad Karsai, Michael C. Fong, Weiliang Cai, J. Gabriel Fraley, Jasper H.N. Yik, Eric Klineberg, Dominik R Haudenschild, Gang Yu Liu

Research output: Contribution to journalArticlepeer-review

Abstract

This work reports the first direct observations of binding and complex formation between transforming growth factor beta 1 (TGF-β1) and cartilage oligomeric matrix protein (COMP) using high-resolution atomic force microscopy (AFM). Each COMP molecule consists of pentamers whose five identical monomeric units bundle at N-termini. From this central point, the five monomers' flexible arms extend outward with C-terminal domains at the distal ends, forming a bouquet-like structure. In commonly used buffer solutions, TGF-β1 molecules typically form homodimers (majority), double dimers (minority), and aggregates (trace amount). Mixing TGF-β1 and COMP leads to rapid binding and complex formation. The TGF-β1/COMP complexes contain one to three COMP and multiple TGF-β1 molecules. For complexes with one COMP, the structure is more compact and less flexible than that of COMP alone. For complexes with two or more COMP molecules, the conformation varies to a large degree from one complex to another. This is attributed to the presence of double dimers or aggregates of TGF-β1 molecules, whose size and multiple binding sites enable binding to more than one COMP. The number and location of individual TGF-β1 dimers are also clearly visible in all complexes. This molecular-level information provides a new insight into the mechanism of chondrogenesis enhancement by TGF-β1/COMP complexes, i.e., simultaneous and multivalent presentation of growth factors. These presentations help explain the high efficacy in sustained activation of the signaling pathway to augment chondrogenesis.

Original languageEnglish (US)
JournalThe journal of physical chemistry. B
DOIs
StateAccepted/In press - 2020

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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