Fully reduced granulin-B is intrinsically disordered and displays concentration-dependent dynamics

Gaurav Ghag, Lauren M. Wolf, Randi G. Reed, Nicholas P. Van Der Munnik, Claudius Mundoma, Melissa A. Moss, Vijayaraghavan Rangachari

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Granulins (Grns) are a family of small, cysteine-rich proteins that are generated upon proteolytic cleavage of their precursor, progranulin (Pgrn). All seven Grns (A-G) contain 12 conserved cysteines that form 6 intramolecular disulfide bonds, rendering this family of proteins unique. Grns are known to play multi-functional roles, including wound healing, embryonic growth, and inflammation and are implicated in neurodegenerative diseases. Despite their manifold functions, there exists a dearth of information regarding their structure-function relationship. Here, we sought to establish the role of disulfide bonds in promoting structure by investigating the fully reduced GrnB (rGrnB). We report that monomeric rGrnB is an intrinsically disordered protein (IDP) at low concentrations. rGrnB undergoes dimerization at higher concentrations to form a fuzzy complex without a net gain in the structure - a behavior increasingly identified as a hallmark of some IDPs. Interestingly, we show that rGrnB is also able to activate NF-κB in human neuroblastoma cells in a concentration-dependent manner. This activation correlates with the observed monomer-dimer dynamics. Collectively, the presented data establish that the intrinsic disorder of rGrnB governs conformational dynamics within the reduced form of the protein, and suggest that the overall structure of Grns could be entirely dictated by disulfide bonds.

Original languageEnglish (US)
Pages (from-to)177-186
Number of pages10
JournalProtein Engineering, Design and Selection
Volume29
Issue number5
DOIs
StatePublished - May 1 2016

Keywords

  • cysteine-rich protein
  • fuzzy complex
  • granulin
  • intrinsically disordered protein
  • progranulin

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biochemistry
  • Molecular Biology

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