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Profilin 1

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PFN1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPFN1, ALS18, Profilin 1
External IDsOMIM: 176610; MGI: 97549; HomoloGene: 3684; GeneCards: PFN1; OMA:PFN1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5216

18643

Ensembl

ENSG00000108518

ENSMUSG00000018293

UniProt

P07737

P62962

RefSeq (mRNA)

NM_005022
NM_001375991

NM_011072

RefSeq (protein)

NP_005013
NP_001362920

NP_035202

Location (UCSC)Chr 17: 4.95 – 4.95 MbChr 11: 70.54 – 70.55 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Profilin-1 is a protein that in humans is encoded by the PFN1 gene.[5][6]

Structure

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The PFN1 protein, also known as profilin-1, is a small, monomeric protein composed of 139–140 amino acids with a molecular mass of approximately 15 kDa.[7] Its three-dimensional structure features an antiparallel, seven-stranded β-sheet core flanked by three amphipathic α-helices—two on one side of the sheet and one on the other—forming a compact, globular fold known as the "profilin-like" fold.[7] PFN1 contains three key functional domains: an actin-binding domain, a poly-L-proline (PLP)-binding domain, and a phosphoinositide-binding domain.[8] These domains enable PFN1 to interact with actin monomers, polyproline-rich motifs in various cytoskeletal proteins, and phosphoinositides, respectively, facilitating its central role in actin cytoskeleton dynamics. Structural studies, including NMR and X-ray crystallography, have shown that PFN1’s binding sites for actin and PLP are distinct and flexible, allowing the protein to adopt different conformations when free or bound to its ligands.[7][9] This structural versatility is essential for PFN1’s function in actin polymerization and its involvement in numerous cellular processes.

Function

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The protein encoded by this gene is a ubiquitously expressed actin monomer-binding protein belonging to the profilin family. It is believed to regulate actin polymerization in response to extracellular signals. Profilin-1 also functions as a pseudouridine-binding protein, contributing to the stability and translational efficiency of certain mRNAs.[10]

Profilin 1 (PFN1) is a highly conserved actin-binding protein that plays a central role in regulating actin polymerization and, consequently, the dynamics of the actin cytoskeleton.[11][12] By binding actin monomers, PFN1 promotes their incorporation into growing actin filaments, thereby influencing key cellular processes such as cell motility, membrane trafficking, endocytosis, cell cycle progression, and cell survival.[12][8]

In addition to its canonical role in actin dynamics, PFN1 interacts with poly-L-proline–rich motifs found in various signaling and cytoskeletal proteins, as well as with phosphoinositide lipids, thereby linking cytoskeletal regulation to intracellular signaling pathways.[12] Recent studies have expanded the known functions of PFN1 to include roles in microtubule organization, mitochondrial homeostasis, and the regulation of autophagy and mitophagy.[12][13]

Disruption of PFN1 function through mutation or loss has been implicated in several diseases, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), as well as various cancers and cardiovascular conditions.[11][8] PFN1 thus acts as a key integrator of cytoskeletal dynamics and intracellular signaling, playing a critical role in maintaining normal cell function and viability.

Clinical significance

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Deletion of this gene is associated with Miller-Dieker syndrome.[14] Mutations in this gene may be a rare cause of amyotrophic lateral sclerosis, also called Lou Gehrig's disease.[15][16][17][18][19][20][21][22][23][24][25][26][27]

Interactions

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Profilin 1 has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000108518 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018293 – 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. ^ Kwiatkowski DJ, Bruns GA (May 1988). "Human profilin. Molecular cloning, sequence comparison, and chromosomal analysis". Journal of Biological Chemistry. 263 (12): 5910–5915. doi:10.1016/S0021-9258(18)60651-9. PMID 3356709.
  6. ^ Kwiatkowski DJ, Aklog L, Ledbetter DH, Morton CC (April 1990). "Identification of the functional profilin gene, its localization to chromosome subband 17p13.3, and demonstration of its deletion in some patients with Miller-Dieker syndrome". American Journal of Human Genetics. 46 (3): 559–567. PMC 1683621. PMID 1968707.
  7. ^ a b c Del Poggetto E, Chiti F, Bemporad F (July 2015). "The Folding process of Human Profilin-1, a novel protein associated with familial amyotrophic lateral sclerosis". Scientific Reports. 5: 12332. Bibcode:2015NatSR...512332D. doi:10.1038/srep12332. PMC 4521207. PMID 26227615.
  8. ^ a b c Wang Y, Wang Y, Wan R, Hu C, Lu Y (July 2021). "Profilin 1 Protein and Its Implications for Cancers". Oncology. 35 (7). Williston Park, N.Y.: 402–409. doi:10.46883/ONC.2021.3507.0402. PMID 34264570.
  9. ^ Kiaei M, Balasubramaniam M, Govind Kumar V, Shmookler Reis RJ, Moradi M, Varughese KI (August 2018). "ALS-causing mutations in profilin-1 alter its conformational dynamics: A computational approach to explain propensity for aggregation". Scientific Reports. 8 (1): 13102. Bibcode:2018NatSR...813102K. doi:10.1038/s41598-018-31199-7. PMC 6117255. PMID 30166578.
  10. ^ Dai X, Yuan J, He S, Shah K, Guo S, Duan Z, et al. (2024-12-31). "Quantitative Proteomics Identifies Profilin-1 as a Pseudouridine-Binding Protein". Journal of the American Chemical Society. 147 (2): 1458–1462. doi:10.1021/jacs.4c17659. ISSN 0002-7863. PMC 11744752. PMID 39812085.
  11. ^ a b Lindamood HL, Liu TM, Read TA, Vitriol EA (March 2025). "Using ALS to understand profilin 1's diverse roles in cellular physiology". Cytoskeleton. 82 (3). Hoboken, N.J.: 111–129. doi:10.1002/cm.21896. PMC 11762371. PMID 39056295.
  12. ^ a b c d Pimm ML, Liu X, Tuli F, Heritz J, Lojko A, Henty-Ridilla JL (June 2022). "Visualizing molecules of functional human profilin". eLife. 11. doi:10.7554/eLife.76485. PMC 9249392. PMID 35666129.
  13. ^ Read TA, Cisterna BA, Skruber K, Ahmadieh S, Liu TM, Vitriol JA, et al. (August 2024). "The actin binding protein profilin 1 localizes inside mitochondria and is critical for their function". EMBO Reports. 25 (8): 3240–3262. doi:10.1038/s44319-024-00209-3. PMC 11316047. PMID 39026010.
  14. ^ "Entrez Gene: PFN1 profilin 1".
  15. ^ Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, et al. (August 2012). "Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis". Nature. 488 (7412): 499–503. Bibcode:2012Natur.488..499W. doi:10.1038/nature11280. PMC 3575525. PMID 22801503.
  16. ^ Daoud H, Dobrzeniecka S, Camu W, Meininger V, Dupré N, Dion PA, et al. (April 2013). "Mutation analysis of PFN1 in familial amyotrophic lateral sclerosis patients". Neurobiology of Aging. 34 (4): 1311.e1–1311.e2. doi:10.1016/j.neurobiolaging.2012.09.001. PMID 23062600. S2CID 42137823.
  17. ^ Tiloca C, Ticozzi N, Pensato V, Corrado L, Del Bo R, Bertolin C, et al. (May 2013). "Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia". Neurobiology of Aging. 34 (5): 1517.e9–1517.10. doi:10.1016/j.neurobiolaging.2012.09.016. PMC 3548975. PMID 23063648.
  18. ^ Ingre C, Landers JE, Rizik N, Volk AE, Akimoto C, Birve A, et al. (June 2013). "A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts". Neurobiology of Aging. 34 (6): 1708.e1–1708.e6. doi:10.1016/j.neurobiolaging.2012.10.009. PMC 6591725. PMID 23141414.
  19. ^ Lattante S, Le Ber I, Camuzat A, Brice A, Kabashi E (June 2013). "Mutations in the PFN1 gene are not a common cause in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration in France". Neurobiology of Aging. 34 (6): 1709.e1–1709.e2. doi:10.1016/j.neurobiolaging.2012.10.026. PMID 23182804. S2CID 37470475.
  20. ^ Dillen L, Van Langenhove T, Engelborghs S, Vandenbulcke M, Sarafov S, Tournev I, et al. (June 2013). "Explorative genetic study of UBQLN2 and PFN1 in an extended Flanders-Belgian cohort of frontotemporal lobar degeneration patients". Neurobiology of Aging. 34 (6): 1711.e1–1711.e5. doi:10.1016/j.neurobiolaging.2012.12.007. PMID 23312802. S2CID 8448562.
  21. ^ Zou ZY, Sun Q, Liu MS, Li XG, Cui LY (June 2013). "Mutations in the profilin 1 gene are not common in amyotrophic lateral sclerosis of Chinese origin". Neurobiology of Aging. 34 (6): 1713.e5–1713.e6. doi:10.1016/j.neurobiolaging.2012.12.024. PMID 23357624. S2CID 9675956.
  22. ^ Chen Y, Zheng ZZ, Huang R, Chen K, Song W, Zhao B, et al. (July 2013). "PFN1 mutations are rare in Han Chinese populations with amyotrophic lateral sclerosis". Neurobiology of Aging. 34 (7): 1922.e1–1922.e5. doi:10.1016/j.neurobiolaging.2013.01.013. PMID 23428184. S2CID 25016105.
  23. ^ van Blitterswijk M, Baker MC, Bieniek KF, Knopman DS, Josephs KA, Boeve B, et al. (September 2013). "Profilin-1 mutations are rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia". Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. 14 (5–6): 463–469. doi:10.3109/21678421.2013.787630. PMC 3923463. PMID 23634771.
  24. ^ Yang S, Fifita JA, Williams KL, Warraich ST, Pamphlett R, Nicholson GA, et al. (September 2013). "Mutation analysis and immunopathological studies of PFN1 in familial and sporadic amyotrophic lateral sclerosis". Neurobiology of Aging. 34 (9): 2235.e7–2235.10. doi:10.1016/j.neurobiolaging.2013.04.003. PMID 23635659. S2CID 19339337.
  25. ^ Fratta P, Charnock J, Collins T, Devoy A, Howard R, Malaspina A, et al. (May 2014). "Profilin1 E117G is a moderate risk factor for amyotrophic lateral sclerosis". Journal of Neurology, Neurosurgery, and Psychiatry. 85 (5): 506–508. doi:10.1136/jnnp-2013-306761. PMC 3995330. PMID 24309268.
  26. ^ Syriani E, Salvans C, Salvadó M, Morales M, Lorenzo L, Cazorla S, et al. (December 2014). "PFN1 mutations are also rare in the Catalan population with amyotrophic lateral sclerosis". Journal of Neurology. 261 (12): 2387–2392. doi:10.1007/s00415-014-7501-x. PMID 25249294. S2CID 21281429.
  27. ^ Smith BN, Vance C, Scotter EL, Troakes C, Wong CH, Topp S, et al. (March 2015). "Novel mutations support a role for Profilin 1 in the pathogenesis of ALS". Neurobiology of Aging. 36 (3): 1602.e17–1602.e27. doi:10.1016/j.neurobiolaging.2014.10.032. PMC 4357530. PMID 25499087.
  28. ^ Yayoshi-Yamamoto S, Taniuchi I, Watanabe T (September 2000). "FRL, a novel formin-related protein, binds to Rac and regulates cell motility and survival of macrophages". Molecular and Cellular Biology. 20 (18): 6872–6881. doi:10.1128/mcb.20.18.6872-6881.2000. PMC 86228. PMID 10958683.
  29. ^ Boettner B, Govek EE, Cross J, Van Aelst L (August 2000). "The junctional multidomain protein AF-6 is a binding partner of the Rap1A GTPase and associates with the actin cytoskeletal regulator profilin". Proceedings of the National Academy of Sciences of the United States of America. 97 (16): 9064–9069. Bibcode:2000PNAS...97.9064B. doi:10.1073/pnas.97.16.9064. PMC 16822. PMID 10922060.
  30. ^ Harbeck B, Hüttelmaier S, Schluter K, Jockusch BM, Illenberger S (October 2000). "Phosphorylation of the vasodilator-stimulated phosphoprotein regulates its interaction with actin". Journal of Biological Chemistry. 275 (40): 30817–30825. doi:10.1074/jbc.M005066200. PMID 10882740.
  31. ^ Miki H, Suetsugu S, Takenawa T (December 1998). "WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac". The EMBO Journal. 17 (23): 6932–6941. doi:10.1093/emboj/17.23.6932. PMC 1171041. PMID 9843499.
  32. ^ Mimuro H, Suzuki T, Suetsugu S, Miki H, Takenawa T, Sasakawa C (September 2000). "Profilin is required for sustaining efficient intra- and intercellular spreading of Shigella flexneri". Journal of Biological Chemistry. 275 (37): 28893–28901. doi:10.1074/jbc.M003882200. PMID 10867004.
  33. ^ Suetsugu S, Miki H, Takenawa T (November 1998). "The essential role of profilin in the assembly of actin for microspike formation". The EMBO Journal. 17 (22): 6516–6526. doi:10.1093/emboj/17.22.6516. PMC 1170999. PMID 9822597.

Further reading

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