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SCRN3

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SCRN3
Identifiers
AliasesSCRN3, SES3, secernin 3
External IDsOMIM: 614967; MGI: 1921866; HomoloGene: 11601; GeneCards: SCRN3; OMA:SCRN3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

79634

74616

Ensembl

ENSG00000144306

ENSMUSG00000008226

UniProt

Q0VDG4
Q0VDG5

Q3TMH2

RefSeq (mRNA)

NM_001193528
NM_024583

NM_029022
NM_001355711

RefSeq (protein)

NP_001180457
NP_078859
NP_078859.2

NP_083298
NP_001342640

Location (UCSC)Chr 2: 174.4 – 174.43 MbChr 2: 73.14 – 73.17 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Secernin-3 (SCRN3) is a protein that is encoded by the human SCRN3 gene. SCRN3 belongs to the peptidase C69 family and the secernin subfamily.[5] As a part of this family, the protein is predicted to enable cysteine-type exopeptidase activity and dipeptidase activity, as well as be involved in proteolysis. It is ubiquitously expressed in the brain, thyroid, and 25 other tissues.[6] Additionally, SCRN3 is conserved in a variety of species, including mammals, birds, fish, amphibians, and invertebrates.[6] SCRN3 is predicted to be an integral component of the cytoplasm.

Gene

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SCRN3 is also commonly known as FLJ23142 and SES3.

Locus

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Human SCRN3 Genetic Locus, found using NCBI Gene

Homo sapiens secernin-3 (SCRN3) is a protein-coding gene. It can be found on chromosome 2, with its specific location being 2q31.1, on the '+' strand.[7][8] The gene is 33,846 base pairs long and contains 8 exons.[7][5]

Transcript

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The most common transcript of the SCRN3 protein-coding gene is transcript variant 1, which is 3052 base pairs long.[7] SCRN3 is expressed at a high level, 2.4 times the average gene in this release.

Human SCRN3 Annotated Conceptual Translation. Translated NM_024583.5 mRNA sequence using Six-Frame Translation tool at Bioline.
Table of Human SCRN3 mRNA isoforms. Sequences and annotations found using isoforms listed in NCBI Gene.1 Isoform name, accession number, and length of isoform transcript are listed on the left in units of nucleotides. Length of each exon is highlighted in yellow for each isoform variant. For Isoforms X1-X3, the BLAT Search Genome from UCSC was utilized in order to determine the locations of the exons within the sequence, in addition to NCBI Gene.

Human SCRN3 has 8 different isoforms.[6]

Expression

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The mRNA of SCRN3 was found to be moderate in humans. SCRN3 is expressed in most major tissues. The mRNA is expressed at slightly elevated levels in the brain, thyroid, heart, and prostate relative to other tissues, though the underlying trend was relatively consistent ubiquitous expression among various tissues.[9][10]

In an analysis of SCRN3 in situ hybridization of both mouse brain and embryo, no specific areas of strong expression were located, instead showing a moderate expression throughout, confirming that SCRN3 likely has ubiquitous expression within most tissues. Immunohistochemistry data also indicated that human SCRN3 has low tissue, single cell, immune cell, and brain region specificity, once again adding to the evidence of ubiquitous expression.[11]

Protein

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Transcript variant 1 of the SCRN3 gene encodes the most common protein isoform, secernin-3 isoform 1, which is 424 amino acids long. The molecular weight of the unmodified SCRN3 protein is approximately 48.413 kDa[12] and the theoretical isoelectric point (pI) of SCRN3 is 5.38.[13] The theoretical isoelectric point, coupled with a predominance of acidic amino acids in the protein's composition, suggest that SCRN3 is a relatively acidic protein.

Additionally, the relative protein abundance of SCRN3 in humans was found to be moderately high compared to other human proteins, at 6.13 ppm.[14]

Domains

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SCRN3 has a single notable domain, identified as the Peptidase_C69 Domain, or PepD domain for short. This domain spans from amino acid position 5 to 226 of the protein. The sequences found within this domain are characteristic of the Peptidase C69 family, and more specifically the Secernin subfamily, known to be mainly dipeptidases. Within this family, comparative sequence and structural analysis revealed a cysteine as the catalytic nucleophile, a feature that can be found on Secernin-3.[5][15]

Structure

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Alphafold predicted tertiary structure for human SCRN3 protein

Within the predicted tertiary structure of SCRN3, the most highly conserved amino acids were found predominantly within the internal portion of the protein. This suggests that the most conserved amino acids, being on the inside, are important to providing the structure of the protein, as well as providing internal functionality.

Localization

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Within the cell, SCRN3 is predicted to be primarily expressed in the cytoplasm.[16][17] The cytoplasmic localization prediction was consistent among 5 additional orthologs (Mauremys reevesii, Gallus gallus, Microcaecilia unicolor, Danio rerio, & Anopheles gambiae), confirming the predicted cytoplasmic subcellular localization of human SCRN3.

Post-Translational Modifications

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Human SCRN3 Predicted Protein Domain, Motif, and Post-Translational Modification diagram. P = Phosphorylation site, U = Ubiquitination site, S = Sumoylation site, L = Lysine-Acetylation site, O = O-beta-GlcNAc attachment site.

SCRN3 is subject to several predicted post-translational modifications, including phosphorylation, ubiquitylation, sumoylation, lysine acetylation, and O-beta-GlcNAc attachment sites, among others.

Additionally, Secernin-3 provided the first example of a predicted naturally occurring N-terminal glyoxylyl (Glox) electrophile through the use of reverse-polarity activity-based protein profiling (RP-ABPP). Using hydrazine probes, it was confirmed that the cysteine (Cys) residue was post-translationally converted to Glox. This identified an electrophilic n-terminal glyoxylyl group for the first time in secernin-3, though the functions of both the protein and Glox as a cofactor have not yet been experimentally validated.[18][19][20]

Homology/Evolution

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Paralogs

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Multiple Sequence alignment of Human SCRN3 protein and its human paralogs, SCRN2 and SCRN1. Dark Shading indicates exact amino acid matches. Light shading indicates close matches. PepD region and exon boundaries determined from Homo sapiens SCRN3 sequence. Made using Clustal Omega

SCRN3 has two known paralogs, SCRN2 and SCRN1, which share a 67.4% and 63.8% similarity to the SCRN3 protein sequence, respectively. Both paralogs are moderately related to SCRN3. SCRN2 was found within the same species groups as SCRN3. SCRN1 was conserved in fewer species groups, including mammals, birds, reptiles, amphibians, and cartilaginous fish, but not in other fish or invertebrates.[21][22]

Orthologs

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Multiple Sequence Alignment of Human SCRN3 protein with identified invertebrate orthologs. Dark Shading indicates exact amino acid matches. Light shading indicates close matches. PepD region and exon boundaries determined from Homo sapiens SCRN3 sequence. Created using Clustal Omega

Over 100 orthologs exist for the human gene SCRN3.[23] The known orthologs were found to exist in vertebrates and invertebrates, but not in plants, bacteria, or fungi. The divergence date of 20 orthologs found were compared relative to Homo sapiens. Invertebrates are the most distantly related orthologs to human SCRN3, with the furthest median date of divergence from this set of orthologs being 694 million years ago.

SCRN3 Orthologs[24]
Genus and Species Common Name Taxonomic Group Median Date of Divergence (MYA) Accession # Sequence Length (aa) Sequence Identity to Human Protein (%) Sequence Similarity to Human Protein (%)
Mammal Homo sapiens Human Primates 0 NP_078859.2 424 100 100
Mus musculus House mouse Rodentia 87 NP_083298.1 418 90.1 93.7
Canis lupus familiaris Dog Carnivora 94 XP_038303032.1 422 80.9 89.9
Gracilinanus agilis Agile Gracile Opossum Didelphimorphia 160 XP_044522430.1 421 74.2 84.5
Tachyglossus aculeatus Australian Echidna Monotremata 180 XP_038607834.1 427 70.5 81.2
Reptilia Mauremys reevesii Reeves' Turtle Testudines 319 XP_039351479.1 424 73.1 82.6
Crocodylus porosus Australian Saltwater Crocodile Crocodylia 319 XP_019409221 423 72.5 82
Varanus komodoensis Komodo Dragon Squamata 319 XP_044273731.1 421 70.3 81.9
Aves Gallus gallus Red Junglefowl (Chicken) Galliformes 319 NP_001244270.2 420 70.7 79.5
Anas platyrhynchos Mallard Anseriformes 319 XP_027317143.2 422 70.1 81
Corvus hawaiiensis Hawaiian Crow Passeriformes 319 XP_048165925.1 420 70 80
Amphibian Microcaecilia unicolor N/A Gymnophiona 353 XP_030064980.1 415 67.8 81.2
Xenopus tropicalis Tropical Clawed Frog Anura 353 XP_002934649.3 410 63.4 74.4
Fish Protopterus annectens West African lungfish Dipnoi 408 XP_043931491.1 420 63.3 75.5
Latimeria chalumnae Coelacanth Coelacanthiformes 414 XP_006003581 431 63.5 75.7
Danio rerio Zebrafish Actinopterygii 431 NP_956032.1 417 61.7 74.2
Callorhinchus milii Elephant Shark Chondrichthyes 464 XP_007888203.1 426 63.2 77.5
Invertebrate Branchiostoma lanceolatum Common Lancelet Cephalochordata 556 CAH1238234.1 434 48 64.4
Trichinella sp. T9 Trichinella Roundworm Nematoda 694 KRX60400.1 418 47.2 62
Trichonephila inaurata madagascariensis Red-Legged Golden Orb-Web Spider Arthropoda 694 GFY76389.1 412 45.4 59.1
Anopheles gambiae African malaria mosquito Arthropoda 694 XP_321103.4 371 29.1 44.1

Evolution

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Graph of Corrected Sequence Divergence vs. Median Date of Divergence. Blue indicates SCRN3. Red indicates SCRN2. Yellow indicates SCRN1. Green indicates Cytochrome C. Orange indicates Fibrinogen Alpha.
SCRN3 time-calibrated unrooted phylogenetic tree. Colored circles indicate taxonomic groupings. Created using Méthodes et Algorithmes pour la Bio-informatique LIRMM “One-Click” Phylogeny Tool

The relative rate of molecular evolution for SCRN3 was moderately high, being slightly lower than the evolution rate of Fibrinogen Alpha, and more rapid than the evolution rate of Cytochrome C. SCRN3 is estimated to have first appeared in invertebrates approximately 694 million years ago, evolving to eventually being found in humans.

Interacting Proteins

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A search of PSCQUIC[25] identified 5 proteins that interact with human SCRN3 protein.

Interacting Protein Protein Full Name Interaction Type Interaction Detection method Experimental Role Cellular Compartment Function
RCVRN Recoverin association, physical association anti tag coimmunoprecipitation, affinity chromatography technology bait cytosol, nucleus, mitochondrion, cytoskeleton, extracellular, plasma membrane Encodes a member of the recoverin family of neuronal calcium sensors. May prolong the termination of the phototransduction cascade in the retina by blocking the phosphorylation of photo-activated rhodopsin.
EPS8 Epidermal Growth Factor Receptor Pathway Substrate 8 colocalization, physical association (x2) confocal microscopy, two hybrid, affinity chromatography technology neutral component, unspecified role cytosol, extracellular, plasma membrane It functions as part of the epidermal growth factor receptor (EGFR) pathway. Signaling adapter that controls various cellular protrusions by regulating actin cytoskeleton dynamics and architecture
MAGOH Mago Homolog, Exon Junction Complex Subunit association, physical association, direct interaction anti tag coimmunoprecipitation, affinity chromatography technology, two hybrid bait nucleus, cytosol Required for pre-mRNA splicing as component of the spliceosome. Core component of the exon junction complex (EJC). The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. Expressed ubiquitously in adult tissues.
DAPK1 Death Associated Protein Kinase 1 direct interaction protein array prey Cytoskeleton, plasma membrane, cytosol, nucleus Positive mediator of gamma-interferon induced programmed cell death. Involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy
SMYD1 SET and MYND Domain Containing 1 association, physical association, direct interaction anti tag coimmunoprecipitation, affinity chromatography technology bait cytoplasm, nucleus Predicted to enable histone-lysine- N-methyltransferase activity. Involved in positive regulation of myoblast differentiation. Predicted to be located in cytoplasm. Acts as a transcriptional repressor.

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000144306 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000008226 – 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.
  5. ^ a b c "SCRN3 Gene - GeneCards | SCRN3 Protein | SCRN3 Antibody". www.genecards.org. Retrieved 2022-09-18.
  6. ^ a b c "SCRN3 secernin 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-18.
  7. ^ a b c "Homo sapiens secernin 3 (SCRN3), transcript variant 1, mRNA". U.S. National Library of Medicine. 2020-12-12.
  8. ^ "CCDS Report for Consensus CDS". www.ncbi.nlm.nih.gov. Retrieved 2022-09-18.
  9. ^ "SCRN3 secernin 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-07.
  10. ^ "GEO Profile Links for Gene (Select 79634) - GEO Profiles - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-07.
  11. ^ "SCRN3 protein expression summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2022-12-07.
  12. ^ "secernin-3 isoform 1 [Homo sapiens] - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-18.
  13. ^ "ExPasy pI Computation Tool".[permanent dead link]
  14. ^ "PAXdb: Protein Abundance Database". pax-db.org. Retrieved 2022-12-07.
  15. ^ Abbasi AA (November 2010). "Unraveling ancient segmental duplication events in human genome by phylogenetic analysis of multigene families residing on HOX-cluster paralogons". Molecular Phylogenetics and Evolution. 57 (2): 836–848. doi:10.1016/j.ympev.2010.07.021. PMID 20696259.
  16. ^ "PSORTII Protein Localization Analysis Tool".[permanent dead link]
  17. ^ "DeepLoc Protein Localization Analysis Tool".
  18. ^ Matthews ML, He L, Horning BD, Olson EJ, Correia BE, Yates JR, et al. (March 2017). "Chemoproteomic profiling and discovery of protein electrophiles in human cells". Nature Chemistry. 9 (3): 234–243. Bibcode:2017NatCh...9..234M. doi:10.1038/nchem.2645. PMC 5325178. PMID 28221344.
  19. ^ Wang X, Lin Z, Bustin KA, McKnight NR, Parsons WH, Matthews ML (March 2022). "Discovery of Potent and Selective Inhibitors against Protein-Derived Electrophilic Cofactors". Journal of the American Chemical Society. 144 (12): 5377–5388. doi:10.1021/jacs.1c12748. PMC 10159212. PMID 35235319. S2CID 247220590.
  20. ^ Dettling SE, Ahmadi M, Lin Z, He L, Matthews ML (December 2020). "Discovery of Electrophiles and Profiling of Enzyme Cofactors". Current Protocols in Chemical Biology. 12 (4): e86. doi:10.1002/cpch.86. PMC 9285064. PMID 33197155.
  21. ^ "SCRN2 secernin 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-07.
  22. ^ "SCRN1 secernin 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-07.
  23. ^ "ortholog_gene_79634[group] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-07.
  24. ^ "ortholog_gene_79634[group - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-10-20.
  25. ^ "PSICQUIC View". www.ebi.ac.uk. Retrieved 2022-12-07.
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