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Cited by 42Protease and Inhibitor MechanismsAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Multi-Granulin Domain Peptides Bind to Pro-Cathepsin D and Stimulate Its Enzymatic Activity More Effectively Than Progranulin in Vitro

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Butler, Victoria J., Cortopassi, Wilian A., Gururaj, Sushmitha, Wang, Austin L., Pierce, Olivia M., Jacobson, Matthew P., Kao, Aimee W.·2019·Biochemistry
DOI 10.1021/acs.biochem.9b00275PMC PMC6666309
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Abstract

Progranulin (PGRN) is an evolutionarily conserved glycoprotein associated with several disease states, including neurodegeneration, cancer, and autoimmune disorders. This protein has recently been implicated in the regulation of lysosome function, whereby PGRN may bind to and promote the maturation and activity of the aspartyl protease cathepsin D (proCTSD, inactive precursor; matCTSD, mature, enzymatically active form). As the full-length PGRN protein can be cleaved into smaller peptides, called granulins, we assessed the function of these granulin peptides in binding to proCTSD and stimulating matCTSD enzyme activity in vitro. Here, we report that full-length PGRN and multi-granulin domain peptides bound to proCTSD with low to submicromolar binding affinities. This binding promoted proCTSD destabilization, the magnitude of which was greater for multi-granulin domain peptides than for full-length PGRN. Such destabilization correlated with enhanced matCTSD activity at acidic pH. The presence and function of multi-granulin domain peptides have typically been overlooked in previous studies. This work provides the first in vitro quantification of their binding and activity on proCTSD. Our study highlights the significance of multi-granulin domain peptides in the regulation of proCTSD maturation and enzymatic activity and suggests that attention to PGRN processing will be essential for the future understanding of the molecular mechanisms leading to neurodegenerative disease states with loss-of-function mutations in PGRN.

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  • The balance between cell proliferation and programmed cell death is altered in LSDs as well as neurodegenerative disorders.

    “The balance between cell proliferation and programmed cell death is altered in LSDs as well as neurodegenerative disorders.26,27”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [26]

    The paper’s Abstract discusses progranulin, lysosomal function, and neurodegenerative disease, and mentions that granulins may affect cell growth. It does not address whether the balance between cell proliferation and programmed cell death is altered in lysosomal storage diseases or neurodegenerative disorders. Searches for that balance and for apoptosis in those diseases found no supporting passage in our copy. (LLM, conf=0.74)

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Research works printed but not linked: 33

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Cited by

Sorted by citations

Authors
Butler, V. J., Cortopassi, W. A., Gururaj, S., Wang, A. L., Pierce, O. M., Jacobson, M. P., & Kao, A. W.
Affiliations
University of California, San Francisco (US)
Corresponding author
  • Jacobson, Matthew P.
  • Kao, Aimee W.
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2019-05-17
Volume
58
Issue
23
Pages
2670-2674
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/acs.biochem.9b00275
PMC
PMC6666309
OpenAlex
W2946706960
Cited by
42
References
2
Citations by year
2026: 4 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 10 · 2020: 5 · 2019: 3
FWCI
1.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Health and Human Services (R01NS095257, R21NS082709, R01AG059052)
  • Emory University
  • Paul G. Allen Family Foundation
  • James and Barbara Knuppe Family Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
progranulin, cathepsin D, procathepsin D, enzyme activation, protein-protein binding, protein destabilization, lysosomal function, neurodegeneration, loss-of-function mutations
MeSH terms
Granulins, Cathepsin D, Enzyme Precursors, Humans, Protein Binding, Protein Conformation, Transition Temperature, Protein Stability

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