Proprotein convertase subtilisin/kexin type 1 inhibitor

PCSK1N
Identifiers
Aliases	PCSK1N, PROSAAS, SAAS, SCG8, SgVIII, BigLEN, PEN, proprotein convertase subtilisin/kexin type 1 inhibitor
External IDs	OMIM: 300399 MGI: 1353431 HomoloGene: 8315 GeneCards: PCSK1N
Gene location (Human)
Chr.	X chromosome (human)[1]
End	48,835,610 bp[1]
Gene location (Mouse)
Chr.	X chromosome (mouse)[2]
End	7,790,649 bp[2]
RNA expression pattern
	Top expressed in
	anterior pituitary; ; nucleus accumbens; ; amygdala; ; caudate nucleus; ; hypothalamus; ; putamen; ; dorsolateral prefrontal cortex; ; Brodmann area 9; ; postcentral gyrus; ; prefrontal cortex;
	Top expressed in
	entorhinal cortex; ; median eminence; ; arcuate nucleus; ; ventromedial nucleus; ; dorsomedial hypothalamic nucleus; ; superior colliculus; ; dorsal tegmental nucleus; ; mammillary body; ; paraventricular nucleus of hypothalamus; ; superior frontal gyrus;
	More reference expression data
	n/a
Gene ontology
Molecular function	endopeptidase inhibitor activity; signaling receptor binding; serine-type endopeptidase inhibitor activity;
Cellular component	extracellular region; trans-Golgi network; Golgi apparatus; secretory granule; extracellular space;
Biological process	response to dietary excess; response to cold; neuropeptide signaling pathway; peptide hormone processing; negative regulation of endopeptidase activity;
	Sources:Amigo / QuickGO
Orthologs
	27344
	30052
	ENSG00000102109
	ENSMUSG00000039278
	Q9UHG2
	Q9QXV0
	NM_013271
	NM_013892
	NP_037403
	NP_038920
	Wikidata
View/Edit Human	View/Edit Mouse

Proprotein convertase subtilisin/kexin type 1 inhibitor is a protein by the name of proSAAS that in humans is encoded by the PCSK1N gene. [5]

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.[6][7] Recent data show that nigral proSAAS expression blocks the deterioration of the striatonigral pathway in a synuclein rat model of Parkinson's disease.[8] ProSAAS also oligomerizes and undergoes liquid-liquid phase separation.[9] Differential expression of this gene may be associated with obesity.

References

GRCh38: Ensembl release 89: ENSG00000102109 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000039278 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Entrez Gene: Proprotein convertase subtilisin/kexin type 1 inhibitor". Retrieved 2017-02-28.
Jarvela TS, Lam HA, Helwig M, Lorenzen N, Otzen DE, McLean PJ, Maidment NT, Lindberg I (2016). "The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity". Proc Natl Acad Sci U S A. 113 (32): E4708-15. Bibcode:2016PNAS..113E4708J. doi:10.1073/pnas.1601091113. PMC 4987805. PMID 27457957.
Hoshino A, Helwig M, Rezaei S, Berridge C, Eriksen JL, Lindberg I (2014). "A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's disease". J Neurochem. 128 (3): 419–30. doi:10.1111/jnc.12454. PMC 3946950. PMID 24102330.
Lindberg I, Shu Z, Lam H, Helwig M, Yucer N, Laperle A, Svendsen CN, Di Monte DA, Maidment NT (2022). "The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease". J Parkinsons Dis. 12 (5): 1463–1478. doi:10.3233/JPD-213053. PMC 9731515. PMID 35527562.
Peinado JR, Chaplot K, Jarvela TS, Barbieri EM, Shorter J, Lindberg I (2022). "Sequestration of TDP-43216-414 Aggregates by Cytoplasmic Expression of the proSAAS Chaperone". ACS Chem Neurosci. 13 (11): 1651–1665. doi:10.1021/acschemneuro.2c00156. PMC 9731516. PMID 35549000.

Fortenberry Y, Hwang JR, Apletalina EV, Lindberg I (2002). "Functional characterization of ProSAAS: similarities and differences with 7B2". J. Biol. Chem. 277 (7): 5175–86. doi:10.1074/jbc.M104531200. PMID 11719503.
Wada M, Ren CH, Koyama S, Arawaka S, Kawakatsu S, Kimura H, Nagasawa H, Kawanami T, Kurita K, Daimon M, Hirano A, Kato T (2004). "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. doi:10.1016/j.neulet.2003.11.028. PMID 14746899. S2CID 46034652.
Kudo H, Liu J, Jansen EJ, Ozawa A, Panula P, Martens GJ, Lindberg I (2009). "Identification of proSAAS homologs in lower vertebrates: conservation of hydrophobic helices and convertase-inhibiting sequences". Endocrinology. 150 (3): 1393–9. doi:10.1210/en.2008-1301. PMC 2654743. PMID 18948394.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000102109 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000039278 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: Proprotein convertase subtilisin/kexin type 1 inhibitor". Retrieved 2017-02-28.

[6] Jarvela TS, Lam HA, Helwig M, Lorenzen N, Otzen DE, McLean PJ, Maidment NT, Lindberg I (2016). "The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity". Proc Natl Acad Sci U S A. 113 (32): E4708-15. Bibcode:2016PNAS..113E4708J. doi:10.1073/pnas.1601091113. PMC 4987805. PMID 27457957.

[7] Hoshino A, Helwig M, Rezaei S, Berridge C, Eriksen JL, Lindberg I (2014). "A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's disease". J Neurochem. 128 (3): 419–30. doi:10.1111/jnc.12454. PMC 3946950. PMID 24102330.

[8] Lindberg I, Shu Z, Lam H, Helwig M, Yucer N, Laperle A, Svendsen CN, Di Monte DA, Maidment NT (2022). "The proSAAS Chaperone Provides Neuroprotection and Attenuates Transsynaptic α-Synuclein Spread in Rodent Models of Parkinson's Disease". J Parkinsons Dis. 12 (5): 1463–1478. doi:10.3233/JPD-213053. PMC 9731515. PMID 35527562.

[9] Peinado JR, Chaplot K, Jarvela TS, Barbieri EM, Shorter J, Lindberg I (2022). "Sequestration of TDP-43216-414 Aggregates by Cytoplasmic Expression of the proSAAS Chaperone". ACS Chem Neurosci. 13 (11): 1651–1665. doi:10.1021/acschemneuro.2c00156. PMC 9731516. PMID 35549000.

Proprotein convertase subtilisin/kexin type 1 inhibitor

Function

References

Further reading