Proprotein convertase subtilisin/kexin type 1 inhibitor explained

Proprotein convertase subtilisin/kexin type 1 inhibitor is a protein by the name of proSAAS that in humans is encoded by the PCSK1N gene.^[1]

Function

This protein is expressed largely in cells possessing a regulated secretory pathway, such as endocrine/neuroendocrine cells and neurons. The intact proSAAS protein, as well as the carboxyy-terminal peptide containing the inhibitory hexapeptide LLRVKR, functions as an inhibitor of prohormone convertase 1/3, which accomplishes the initial proteolytic cleavage of peptide precursors. ProSAAS is further processed at the N- and C-termini into multiple short peptides, leaving the central segment intact. This central, unprocessed portion of the protein may function as a neural- and endocrine-specific chaperone due to its potent ability to block the aggregation of beta amyloid and alpha synuclein in vitro, and to block oligomer cytotoxicity in cells.^{[2] [3]} Recent data show that nigral proSAAS expression blocks the deterioration of the striatonigral pathway in a synuclein rat model of Parkinson's disease.^[4] ProSAAS also oligomerizes and undergoes liquid-liquid phase separation.^[5] Differential expression of this gene may be associated with obesity.

Further reading

• Fortenberry Y, Hwang JR, Apletalina EV, Lindberg I . Functional characterization of ProSAAS: similarities and differences with 7B2 . J. Biol. Chem. . 277 . 7 . 5175–86 . 2002 . 11719503 . 10.1074/jbc.M104531200 . free .
• Wada M, Ren CH, Koyama S, Arawaka S, Kawakatsu S, Kimura H, Nagasawa H, Kawanami T, Kurita K, Daimon M, Hirano A, Kato T . A human granin-like neuroendocrine peptide precursor (proSAAS) immunoreactivity in tau inclusions of Alzheimer's disease and parkinsonism-dementia complex on Guam . Neurosci. Lett. . 356 . 1 . 49–52 . 2004 . 14746899 . 10.1016/j.neulet.2003.11.028. 46034652 .
• Kudo H, Liu J, Jansen EJ, Ozawa A, Panula P, Martens GJ, Lindberg I . Identification of proSAAS homologs in lower vertebrates: conservation of hydrophobic helices and convertase-inhibiting sequences . Endocrinology . 150 . 3 . 1393–9 . 2009 . 18948394 . 2654743 . 10.1210/en.2008-1301 .

Notes and References

1. Web site: Entrez Gene: Proprotein convertase subtilisin/kexin type 1 inhibitor. 2017-02-28.
2. 27457957 . 10.1073/pnas.1601091113 . 113 . 32 . The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity . 4987805 . 2016 . Proc Natl Acad Sci U S A . E4708-15 . Jarvela TS, Lam HA, Helwig M, Lorenzen N, Otzen DE, McLean PJ, Maidment NT, Lindberg I . 2016PNAS..113E4708J . free .
3. 24102330 . 10.1111/jnc.12454 . 128 . 3 . A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's disease . 3946950 . 2014 . J Neurochem . 419–30 . Hoshino A, Helwig M, Rezaei S, Berridge C, Eriksen JL, Lindberg I .
4. 35527562 . 10.3233/JPD-213053 . 12 . 5 . The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease.. 9731515 . 2022 . J Parkinsons Dis. 1463–1478 . Lindberg I, Shu Z, Lam H, Helwig M, Yucer N, Laperle A, Svendsen CN, Di Monte DA, Maidment NT.
5. 35549000 . 10.1021/acschemneuro.2c00156. 13 . 11 . Sequestration of TDP-43216-414 Aggregates by Cytoplasmic Expression of the proSAAS Chaperone.. 9731516 . 2022 . ACS Chem Neurosci. 1651–1665 . Peinado JR, Chaplot K, Jarvela TS, Barbieri EM, Shorter J, Lindberg I.