New insights into the role of Methionine 199 in the function of Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and bone homeostasis

Research output: ThesisMaster's Thesis

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Abstract

Receptor activator of NF-kB ligand (RANKL) is a critical cytokine for osteoclast differentiation, while its mutants have not been well characterized. A natural mutation in human RANKL at residue M199 was described in patients with osteoclast­ poor autosomal recessive osteopetrosis. We generated three RANKLmutants using site directed mutagenesis and studied their efficacy on osteoclastic activity. We found that RANKLmutants exhibit a drastically reduced ability to induce osteoclast formation, osteoclastic polarization, bone resorption as well as downstream signaling due to misfolded RANKL. Our results show that M199 is a structurally-sensitive residue representative of a curative motif for next-generation anti-resorptive drugs.
Original languageEnglish
QualificationMasters
Awarding Institution
  • The University of Western Australia
Supervisors/Advisors
  • Xu, Jiake, Supervisor
  • Pavlos, Nathan, Supervisor
  • Tickner, Jennifer, Supervisor
Award date14 May 2018
DOIs
Publication statusPublished - 2018

Fingerprint

Activator Appliances
RANK Ligand
Osteoclasts
Methionine
Homeostasis
Bone and Bones
Osteopetrosis
NF-kappa B
Bone Resorption
Site-Directed Mutagenesis
Cytokines
Ligands
Mutation
Pharmaceutical Preparations

Cite this

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title = "New insights into the role of Methionine 199 in the function of Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and bone homeostasis",
abstract = "Receptor activator of NF-kB ligand (RANKL) is a critical cytokine for osteoclast differentiation, while its mutants have not been well characterized. A natural mutation in human RANKL at residue M199 was described in patients with osteoclast­ poor autosomal recessive osteopetrosis. We generated three RANKLmutants using site directed mutagenesis and studied their efficacy on osteoclastic activity. We found that RANKLmutants exhibit a drastically reduced ability to induce osteoclast formation, osteoclastic polarization, bone resorption as well as downstream signaling due to misfolded RANKL. Our results show that M199 is a structurally-sensitive residue representative of a curative motif for next-generation anti-resorptive drugs.",
keywords = "RANKL, Mutant, M199, Osteoclasts, Signal transduction, Protein structures, Antibody",
author = "Heng Qiu",
year = "2018",
doi = "10.4225/23/5b2ca0ec6bc71",
language = "English",
school = "The University of Western Australia",

}

TY - THES

T1 - New insights into the role of Methionine 199 in the function of Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) and bone homeostasis

AU - Qiu, Heng

PY - 2018

Y1 - 2018

N2 - Receptor activator of NF-kB ligand (RANKL) is a critical cytokine for osteoclast differentiation, while its mutants have not been well characterized. A natural mutation in human RANKL at residue M199 was described in patients with osteoclast­ poor autosomal recessive osteopetrosis. We generated three RANKLmutants using site directed mutagenesis and studied their efficacy on osteoclastic activity. We found that RANKLmutants exhibit a drastically reduced ability to induce osteoclast formation, osteoclastic polarization, bone resorption as well as downstream signaling due to misfolded RANKL. Our results show that M199 is a structurally-sensitive residue representative of a curative motif for next-generation anti-resorptive drugs.

AB - Receptor activator of NF-kB ligand (RANKL) is a critical cytokine for osteoclast differentiation, while its mutants have not been well characterized. A natural mutation in human RANKL at residue M199 was described in patients with osteoclast­ poor autosomal recessive osteopetrosis. We generated three RANKLmutants using site directed mutagenesis and studied their efficacy on osteoclastic activity. We found that RANKLmutants exhibit a drastically reduced ability to induce osteoclast formation, osteoclastic polarization, bone resorption as well as downstream signaling due to misfolded RANKL. Our results show that M199 is a structurally-sensitive residue representative of a curative motif for next-generation anti-resorptive drugs.

KW - RANKL

KW - Mutant

KW - M199

KW - Osteoclasts

KW - Signal transduction

KW - Protein structures

KW - Antibody

U2 - 10.4225/23/5b2ca0ec6bc71

DO - 10.4225/23/5b2ca0ec6bc71

M3 - Master's Thesis

ER -