Heterodimerization of the Sialidase NEU1 with the Chaperone Protective Protein/Cathepsin A Prevents Its Premature Oligomerization
Open accessAbstract
Lysosomal neuraminidase-1 (NEU1) forms a multienzyme complex with beta-galactosidase and protective protein/cathepsin A (PPCA). Because of its association with PPCA, which acts as a molecular chaperone, NEU1 is transported to the lysosomal compartment, catalytically activated, and stabilized. However, the mode(s) of association between these two proteins both en route to the lysosome and in the multienzyme complex has remained elusive. Here, we have analyzed the hydrodynamic properties of PPCA, NEU1, and a complex of the two proteins and identified multiple binding sites on both proteins. One of these sites on NEU1 that is involved in binding to PPCA can also bind to other NEU1 molecules, albeit with lower affinity. Therefore, in the absence of PPCA, as in the lysosomal storage disease galactosialidosis, NEU1 self-associates into chain-like oligomers. Binding of PPCA can reverse self-association of NEU1 by causing the disassembly of NEU1-oligomers and the formation of a PPCA-NEU1 heterodimeric complex. The identification of binding sites between the two proteins allowed us to create innovative structural models of the NEU1 oligomer and the PPCA-NEU1 heterodimeric complex. The proposed mechanism of interaction between NEU1 and its accessory protein PPCA provides a rationale for the secondary deficiency of NEU1 in galactosialidosis.
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PPCA functions as an indispensable chaperone/auxiliary transport protein, especially for NEU1, which is catalytically inert without PPCA, and PPCA prevents self-aggregation of NEU1 molecules.
“It is nonetheless genetically and biochemically proven that PPCA functions as an indispensable chaperone/auxiliary transport protein, especially for NEU1, that is catalytically inert without PPCA.”
From Galactosialidosis: historic aspects and overview of investigated and emerging treatment options (2017) · cites this paper as [42]
The paper describes PPCA as a crucial chaperone and transport protein for NEU1 and says it promotes NEU1’s lysosomal localization while preventing its clustering (introduction; Complex Formation between PPCA and NEU1; page numbers unavailable). The Results say NEU1 gains full catalytic activity through association with PPCA, but do not establish the stronger claim that NEU1 is completely catalytically inert without it. (LLM, conf=0.87)
Experimental — accuracy not yet measuredGLB1 is not necessary for NEU1 activity and may compete with NEU1 for access to CTSA.
“Whereas a third enzyme—the glycosidase GLB1—has often been reported as a member of the high–molecular weight NEU1-CTSA complex (15, 27), GLB1 is not necessary for NEU1 activity (12, 21–24, 27, 32) and may compete with NEU1 for access to CTSA (12, 32).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [23]
The Results (page not available) show that purified PPCA activates NEU1 in a cell-free assay without GLB1, supporting that GLB1 is not necessary for activity in that setting. The Discussion (page not available) describes PPCA and NEU1 competing for binding sites on other NEU1 molecules; it does not say that GLB1 competes with NEU1 for access to PPCA. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNEU1 is unique among all known sialidases in that it requires an accessory protein for activity.
“NEU1 is unique among all known mammalian, microbial, or viral sialidases, as it requires an accessory protein for activity—the protective protein cathepsin A (CTSA; PPCA) (12, 19–23).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [23]
The Results section says NEU1 gains full catalytic activity through binding to PPCA, supporting its need for that accessory protein. The passages do not establish the broader claim that NEU1 is unique in this respect among all known mammalian, microbial, and viral sialidases. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCTSA is sufficient for NEU1 activity, whereas GLB1 is not necessary.
“However, CTSA is sufficient for NEU1 activity, whereas GLB1 is not necessary (12, 21–24, 27, 32).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [23]
NEU1 requires an accessory protein for activity-the protective protein cathepsin A (CTSA; PPCA).
“NEU1 is unique among all known mammalian, microbial, or viral sialidases, as it requires an accessory protein for activity—the protective protein cathepsin A (CTSA; PPCA) (12, 19–23).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [23]
Coincubation of NEU1 and CTSA was reported to produce a 104-kDa heterodimeric complex with one NEU1 and one CTSA copy.
“Coincubation of both proteins was reported to produce a 104-kDa heterodimeric complex with one NEU1 and one CTSA copy (23), implying that both NEU1 self-association interfaces, as well as the CTSA homodimer, dissociate to allow complex formation.”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [23]
NEU1 is not activated via proteolysis.
“Although CTSA also functions as a protease, NEU1 is not activated via proteolysis (23, 24, 30, 80).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [23]
Isolated CTSA was dimeric, and isolated NEU1 adopted multiple oligomeric states.
“Similar to the current results, isolated CTSA was dimeric, and isolated NEU1 adopted multiple oligomeric states.”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [23]
The binding affinity between NEU1 and CTSA is weak, failing to reach saturation even at high CTSA concentration.
“As previously reported (23), their binding affinity is weak, failing to reach saturation even at high CTSA concentration (Fig. 1C).”
From Structure of the immunoregulatory sialidase NEU1 (2023) · cites this paper as [23]
The Results section reports that NEU1–PPCA binding is minimal at neutral pH and increases as pH decreases; it also compares mutant PPCA affinities with wild-type PPCA. Neither passage establishes that NEU1–CTSA affinity is generally weak or that binding fails to saturate at high CTSA concentrations. Searches for saturation and concentration-dependent affinity found no passage addressing that claim. (LLM, conf=0.70)
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Cites
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Martí-Renom, M. A., Stuart, A. C., Fiser, A., Sánchez, R., Melo, F., & Šali, A. (2000) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.biophys.29.1.291 · Cited by 3,169 · see citing works
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Flagged first, then by citations
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- [1]1. Saito, M., and Yu, R. K. (1995) in Biology of the Sialic Acids (Rosenberg, A., ed) Plenum Press, New York
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Galactosialidosis: historic aspects and overview of investigated and emerging treatment options
Annunziata, I., & d’Azzo, A. (2017) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2016.1266933 · Cited by 50 · see citing works
Self-citationStructure of the immunoregulatory sialidase NEU1
Gorelik, A., Illes, K., Mazhab-Jafari, M. T., & Nagar, B. (2023) · Science Advances · doi:10.1126/sciadv.adf8169 · Cited by 36 · see citing works
Targeting Lysosomal Dysfunction to Alleviate Plaque Deposition in an Alzheimer Disease Model
Fremuth, L. E., van de Vlekkert, D., Hu, H., Weesner, J. A., Annunziata, I., Yogalingam, G., & d’Azzo, A. (2025) · doi:10.1101/2025.04.28.651121 · Cited by 1 · see citing works
Self-citation
- Authors
- Bonten, E. J., Campos, Y., Zaitsev, V., Nourse, A., Waddell, B., Lewis, W., Taylor, G., & d'Azzo, A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of St Andrews (GB)
- Corresponding author
- Bonten, Erik J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 284
- Issue
- 41
- Pages
- 28430-28441
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2788892
- OpenAlex
- W2152929735
- Cited by
- 87
- References
- 2
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 4 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 4 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 6 · 2014: 5 · 2013: 5 · 2012: 9
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM60905, DK52025)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- NEU1, neuraminidase, PpcA, heterodimerization, protein oligomerization, molecular chaperones, galactosialidosis, protein-protein binding sites, lysosomal storage disease, protein complex structure
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Enzyme Activation, Fibroblasts, Humans, Macrophages, Molecular Sequence Data, Neuraminidase, Protein Conformation, Mutagenesis, Site-Directed, Mice, Knockout, Molecular Chaperones, Cathepsin A, Multiprotein Complexes, Mice, Protein Multimerization
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