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

Title: Fully reduced granulin-B is intrinsically disordered and displays concentration-dependent dynamics.
Name(s): Ghag, Gaurav, author
Wolf, Lauren M, author
Reed, Randi G, author
Van Der Munnik, Nicholas P, author
Mundoma, Claudius, author
Moss, Melissa A, author
Rangachari, Vijayaraghavan, author
Type of Resource: text
Genre: Journal Article
Date Issued: 2016-05-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_pmch_26957645 (IID), 10.1093/protein/gzw005 (DOI), PMC4830411 (PMCID), 26957645 (RID), 26957645 (EID), gzw005 (PII)
Keywords: Cysteine-rich protein, Fuzzy complex, Granulin, Intrinsically disordered protein, Progranulin
Grant Number: P20 GM103476, R15 AG046915, P20GM103641, P20 GM103641, 8 P20 GM103476-11, 5P20RR016476-11
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at
Subject(s): Cell Line, Tumor
Conserved Sequence
Intercellular Signaling Peptides and Proteins/chemistry
Intercellular Signaling Peptides and Proteins/metabolism
Intrinsically Disordered Proteins/chemistry
Intrinsically Disordered Proteins/metabolism
NF-kappa B/metabolism
Protein Multimerization
Protein Structure, Quaternary
Persistent Link to This Record:
Host Institution: FSU
Is Part Of: Protein engineering, design & selection : PEDS.
Issue: iss. 5, vol. 29

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Ghag, G., Wolf, L. M., Reed, R. G., Van Der Munnik, N. P., Mundoma, C., Moss, M. A., & Rangachari, V. (2016). Fully reduced granulin-B is intrinsically disordered and displays concentration-dependent dynamics. Protein Engineering, Design & Selection : Peds. Retrieved from