3law

Structural highlights

Disease

[RAB7A_HUMAN] Defects in RAB7A are the cause of Charcot-Marie-Tooth disease type 2B (CMT2B) [MIM:600882]; also known as hereditary motor and sensory neuropathy II (HMSN2). CMT2B is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathy or CMT1, and primary peripheral axonal neuropathy or CMT2. Neuropathies of the CMT2 group are characterized by signs of axonal regeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2B is clinically characterized by marked distal muscle weakness and a high frequency of foot ulcers, infections and amputations of the toes. CMT2B inheritance is autosomal dominant.^{[1] [2] [3] [4]}

Function

[RAB7A_HUMAN] Key regulator in endo-lysosomal trafficking. Governs early-to-late endosomal maturation, microtubule minus-end as well as plus-end directed endosomal migration and positioning, and endosome-lysosome transport through different protein-protein interaction cascades. Plays a central role, not only in endosomal traffic, but also in many other cellular and physiological events, such as growth-factor-mediated cell signaling, nutrient-transportor mediated nutrient uptake, neurotrophin transport in the axons of neurons and lipid metabolism. Also involved in regulation of some specialized endosomal membrane trafficking, such as maturation of melanosomes, pathogen-induced phagosomes (or vacuoles) and autophagosomes. Plays a role in the maturation and acidification of phagosomes that engulf pathogens, such as S.aureus and M.tuberculosis. Plays a role in the fusion of phagosomes with lysosomes. Plays important roles in microbial pathogen infection and survival, as well as in participating in the life cycle of viruses. Microbial pathogens possess survival strategies governed by RAB7A, sometimes by employing RAB7A function (e.g. Salmonella) and sometimes by excluding RAB7A function (e.g. Mycobacterium). In concert with RAC1, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. Controls the endosomal trafficking and neurite outgrowth signaling of NTRK1/TRKA. Regulates the endocytic trafficking of the EGF-EGFR complex by regulating its lysosomal degradation.^{[5] [6] [7] [8]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Verhoeven K, De Jonghe P, Coen K, Verpoorten N, Auer-Grumbach M, Kwon JM, FitzPatrick D, Schmedding E, De Vriendt E, Jacobs A, Van Gerwen V, Wagner K, Hartung HP, Timmerman V. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet. 2003 Mar;72(3):722-7. Epub 2003 Jan 21. PMID:12545426 doi:S0002-9297(07)60588-6
2. ↑ Houlden H, King RH, Muddle JR, Warner TT, Reilly MM, Orrell RW, Ginsberg L. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann Neurol. 2004 Oct;56(4):586-90. PMID:15455439 doi:10.1002/ana.20281
3. ↑ Meggouh F, Bienfait HM, Weterman MA, de Visser M, Baas F. Charcot-Marie-Tooth disease due to a de novo mutation of the RAB7 gene. Neurology. 2006 Oct 24;67(8):1476-8. PMID:17060578 doi:67/8/1476
4. ↑ BasuRay S, Mukherjee S, Romero E, Wilson MC, Wandinger-Ness A. Rab7 mutants associated with Charcot-Marie-Tooth disease exhibit enhanced NGF-stimulated signaling. PLoS One. 2010 Dec 9;5(12):e15351. doi: 10.1371/journal.pone.0015351. PMID:21151572 doi:10.1371/journal.pone.0015351
5. ↑ Cantalupo G, Alifano P, Roberti V, Bruni CB, Bucci C. Rab-interacting lysosomal protein (RILP): the Rab7 effector required for transport to lysosomes. EMBO J. 2001 Feb 15;20(4):683-93. PMID:11179213 doi:10.1093/emboj/20.4.683
6. ↑ Harrison RE, Bucci C, Vieira OV, Schroer TA, Grinstein S. Phagosomes fuse with late endosomes and/or lysosomes by extension of membrane protrusions along microtubules: role of Rab7 and RILP. Mol Cell Biol. 2003 Sep;23(18):6494-506. PMID:12944476
7. ↑ Stein MP, Feng Y, Cooper KL, Welford AM, Wandinger-Ness A. Human VPS34 and p150 are Rab7 interacting partners. Traffic. 2003 Nov;4(11):754-71. PMID:14617358
8. ↑ Seto S, Tsujimura K, Koide Y. Rab GTPases regulating phagosome maturation are differentially recruited to mycobacterial phagosomes. Traffic. 2011 Apr;12(4):407-20. doi: 10.1111/j.1600-0854.2011.01165.x. Epub 2011 , Feb 21. PMID:21255211 doi:10.1111/j.1600-0854.2011.01165.x
9. ↑ McCray BA, Skordalakes E, Taylor JP. Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation. Hum Mol Genet. 2010 Mar 15;19(6):1033-47. Epub 2009 Dec 22. PMID:20028791 doi:10.1093/hmg/ddp567