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

6 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Disulfides
Proteins
Cysteine
Inosine Diphosphate
Intrinsically Disordered Proteins
Neurodegenerative diseases
Dimerization
Neuroblastoma
Neurodegenerative Diseases
Dimers
Wound Healing
Monomers
Chemical activation
Inflammation
granulin 3
granulin precursor protein
Growth

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Medicine(all)
  • Biochemistry
  • Molecular Biology

Cite this

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 and Selection, 29(5), 177-186. https://doi.org/10.1093/protein/gzw005

Fully reduced granulin-B is intrinsically disordered and displays concentration-dependent dynamics. / Ghag, Gaurav; Wolf, Lauren M.; Reed, Randi G.; Van Der Munnik, Nicholas P.; Mundoma, Claudius; Moss, Melissa A.; Rangachari, Vijayaraghavan.

In: Protein Engineering, Design and Selection, Vol. 29, No. 5, 01.05.2016, p. 177-186.

Research output: Contribution to journalArticle

Ghag, G, Wolf, LM, Reed, RG, Van Der Munnik, NP, Mundoma, C, Moss, MA & Rangachari, V 2016, 'Fully reduced granulin-B is intrinsically disordered and displays concentration-dependent dynamics', Protein Engineering, Design and Selection, vol. 29, no. 5, pp. 177-186. https://doi.org/10.1093/protein/gzw005
Ghag, Gaurav ; Wolf, Lauren M. ; Reed, Randi G. ; Van Der Munnik, Nicholas P. ; Mundoma, Claudius ; Moss, Melissa A. ; Rangachari, Vijayaraghavan. / Fully reduced granulin-B is intrinsically disordered and displays concentration-dependent dynamics. In: Protein Engineering, Design and Selection. 2016 ; Vol. 29, No. 5. pp. 177-186.
@article{0222a80819f444c793222c1d3ba89301,
title = "Fully reduced granulin-B is intrinsically disordered and displays concentration-dependent dynamics",
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.",
keywords = "cysteine-rich protein, fuzzy complex, granulin, intrinsically disordered protein, progranulin",
author = "Gaurav Ghag and Wolf, {Lauren M.} and Reed, {Randi G.} and {Van Der Munnik}, {Nicholas P.} and Claudius Mundoma and Moss, {Melissa A.} and Vijayaraghavan Rangachari",
year = "2016",
month = "5",
day = "1",
doi = "10.1093/protein/gzw005",
language = "English (US)",
volume = "29",
pages = "177--186",
journal = "Protein Engineering, Design and Selection",
issn = "1741-0126",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Fully reduced granulin-B is intrinsically disordered and displays concentration-dependent dynamics

AU - Ghag, Gaurav

AU - Wolf, Lauren M.

AU - Reed, Randi G.

AU - Van Der Munnik, Nicholas P.

AU - Mundoma, Claudius

AU - Moss, Melissa A.

AU - Rangachari, Vijayaraghavan

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - cysteine-rich protein

KW - fuzzy complex

KW - granulin

KW - intrinsically disordered protein

KW - progranulin

UR - http://www.scopus.com/inward/record.url?scp=84965079118&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84965079118&partnerID=8YFLogxK

U2 - 10.1093/protein/gzw005

DO - 10.1093/protein/gzw005

M3 - Article

C2 - 26957645

AN - SCOPUS:84965079118

VL - 29

SP - 177

EP - 186

JO - Protein Engineering, Design and Selection

JF - Protein Engineering, Design and Selection

SN - 1741-0126

IS - 5

ER -