6ekk

Structural highlights

Disease

[DEN1A_HUMAN] Genetic variants in DENND1A may play a role in susceptibility to polycystic ovary syndrome (PCOS), the most common endocrine disease among premenopausal women. PCOS is a complex disorder characterized by infertility, hirsutism, obesity, various menstrual disturbances, and enlarged ovaries studded with atretic follicles.^{[1] [2] [3] [4]}

Function

[DEN1A_HUMAN] Guanine nucleotide exchange factor (GEF) regulating clathrin-mediated endocytosis through RAB35 activation. Promotes the exchange of GDP to GTP, converting inactive GDP-bound RAB35 into its active GTP-bound form. Regulates clathrin-mediated endocytosis of synaptic vesicles and mediates exit from early endosomes (PubMed:20154091, PubMed:20937701). Binds phosphatidylinositol-phosphates (PtdInsPs), with some preference for PtdIns(3)P (By similarity).[UniProtKB:Q8K382]^{[5] [6]} [RAB35_HUMAN] The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. That Rab is involved in the process of endocytosis and is an essential rate-limiting regulator of the fast recycling pathway back to the plasma membrane. During cytokinesis, required for the postfurrowing terminal steps, namely for intercellular bridge stability and abscission, possibly by controlling phosphatidylinositol 4,5-bis phosphate (PIP2) and SEPT2 localization at the intercellular bridge. May indirectly regulate neurite outgrowth.^{[7] [8]}

See Also

• GTP-binding protein 3D structures
• Ras-related protein Rab 3D structures

References

1. ↑ Goodarzi MO, Jones MR, Li X, Chua AK, Garcia OA, Chen YD, Krauss RM, Rotter JI, Ankener W, Legro RS, Azziz R, Strauss JF 3rd, Dunaif A, Urbanek M. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet. 2012 Feb;49(2):90-5. doi: 10.1136/jmedgenet-2011-100427. Epub 2011, Dec 17. PMID:22180642 doi:http://dx.doi.org/10.1136/jmedgenet-2011-100427
2. ↑ Cui L, Zhao H, Zhang B, Qu Z, Liu J, Liang X, Zhao X, Zhao J, Sun Y, Wang P, Li T, Shi Y, Chen ZJ. Genotype-phenotype correlations of PCOS susceptibility SNPs identified by GWAS in a large cohort of Han Chinese women. Hum Reprod. 2013 Feb;28(2):538-44. doi: 10.1093/humrep/des424. Epub 2012 Dec 2. PMID:23208300 doi:http://dx.doi.org/10.1093/humrep/des424
3. ↑ Eriksen MB, Nielsen MF, Brusgaard K, Tan Q, Andersen MS, Glintborg D, Gaster M. Genetic alterations within the DENND1A gene in patients with polycystic ovary syndrome (PCOS). PLoS One. 2013 Sep 27;8(9):e77186. doi: 10.1371/journal.pone.0077186. eCollection, 2013. PMID:24086769 doi:http://dx.doi.org/10.1371/journal.pone.0077186
4. ↑ Gammoh E, Arekat MR, Saldhana FL, Madan S, Ebrahim BH, Almawi WY. DENND1A gene variants in Bahraini Arab women with polycystic ovary syndrome. Gene. 2015 Apr 10;560(1):30-3. doi: 10.1016/j.gene.2015.01.034. Epub 2015 Jan 24. PMID:25626177 doi:http://dx.doi.org/10.1016/j.gene.2015.01.034
5. ↑ Marat AL, McPherson PS. The connecdenn family, Rab35 guanine nucleotide exchange factors interfacing with the clathrin machinery. J Biol Chem. 2010 Apr 2;285(14):10627-37. doi: 10.1074/jbc.M109.050930. Epub 2010, Feb 12. PMID:20154091 doi:http://dx.doi.org/10.1074/jbc.M109.050930
6. ↑ Yoshimura S, Gerondopoulos A, Linford A, Rigden DJ, Barr FA. Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors. J Cell Biol. 2010 Oct 18;191(2):367-81. doi: 10.1083/jcb.201008051. Epub 2010 Oct, 11. PMID:20937701 doi:http://dx.doi.org/10.1083/jcb.201008051
7. ↑ Kouranti I, Sachse M, Arouche N, Goud B, Echard A. Rab35 regulates an endocytic recycling pathway essential for the terminal steps of cytokinesis. Curr Biol. 2006 Sep 5;16(17):1719-25. PMID:16950109 doi:http://dx.doi.org/10.1016/j.cub.2006.07.020
8. ↑ Rahajeng J, Giridharan SS, Cai B, Naslavsky N, Caplan S. MICAL-L1 is a tubular endosomal membrane hub that connects Rab35 and Arf6 with Rab8a. Traffic. 2012 Jan;13(1):82-93. doi: 10.1111/j.1600-0854.2011.01294.x. Epub 2011, Oct 24. PMID:21951725 doi:http://dx.doi.org/10.1111/j.1600-0854.2011.01294.x