PXD055848-1

PXD055848 is an original dataset announced via ProteomeXchange.

Title	Activation mechanism of Small Heat Shock Protein HSPB5 revealed by disease-associated mutants.
Description	Found from bacteria to humans, small heat shock proteins (sHSPs) are the least understood protein chaperones. HSPB5 (or αB-crystallin) is among the most widely expressed of the 10 human sHSPs, including in muscle, brain, and eye lens where it is constitutively present at high levels. A high content of disorder in HSPB5 has stymied efforts to uncover how its structure gives rise to function. To uncover its mechanisms of action, we compared human HSPB5 and two disease-associated mutants, R120G and D109H. Expecting to learn how the mutations lead to loss of function, we found nstead that the mutants are constitutively activated chaperones while wild-type HSPB5 can transition reversibly between nonactivated (low activity) and activated (high activity) states in response to changing conditions. Techniques that provide information regarding interactions and accessibility of disordered regions revealed that the disordered N-terminal regions (NTR) that are required for chaperone activity exist in a complicated interaction network within HSPB5 oligomers and are sequestered from solvent in nonactivated states. Either mutation or an activating pH change causes rearrangements in the network that expose parts of the NTR, making them more available to bind an aggregating client. While beneficial in the short-term, failure of the mutants to adopt a state with lower activity and lower NTR accessibility leads to increased coaggregation propensity and, presumably, early cataract. The results support a model where chaperone activity and solubility are modulated through the quasi-ordered NTR and its multiple competing interactions.
HostingRepository	PRIDE
AnnounceDate	2025-04-22
AnnouncementXML	Submission_2025-04-22_13:19:40.313.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lindsey D. Ulmer
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-13 05:35:16	ID requested
⏵ 1	2025-04-22 13:19:40	announced

10.1073/PNAS.2425061122;

submitter keyword: small heat shock proteins, crosslinking mass spectrometry

Matthew F.
contact affiliation	University of Washington Department of Chemistry
contact email	mattbush@uw.edu
lab head
Lindsey D. Ulmer
contact affiliation	University of Washington Department of Chemistry
contact email	lulmer@uw.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055848
     1. Label: PRIDE project
     2. Name: Activation mechanism of Small Heat Shock Protein HSPB5 revealed by disease-associated mutants.