RAB27

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RAB27A, member RAS oncogene family
Identifiers
Symbol RAB27A
NCBI gene 5873
HGNC 9766
OMIM 603868
RefSeq NM_004580
UniProt P51159
Other data
Locus Chr. 15 q21
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Structures Swiss-model
Domains InterPro
RAB27B, member RAS oncogene family
Identifiers
SymbolRAB27B
NCBI gene 5874
HGNC 9767
OMIM 603869
RefSeq NM_004163
UniProt O00194
Other data
Locus Chr. 18 q21.2
Search for
Structures Swiss-model
Domains InterPro

Rab27 is a member of the Rab subfamily of GTPases. Rab27 is post translationally modified by the addition of two geranylgeranyl groups on the two C-terminal cysteines.

Contents

Isoforms

Rab27 has two main isoforms: Rab27a and Rab27b. These are similar in primary composition, with 66% similarity between nucleotides. [1] Most of their differences originate from their C-terminal, which is responsible for interactions with proteins such as SPIREs. [1] [2] Thus, these isoforms play different roles in the regulation pathway of exocytosis. Throughout the process of exocytosis, Rab27a and Rab27b are found in different sections of the cell, with Rab27b found commonly in the TGN and Rab27a usually bound to multivesicular endosomes with CD63 present. [3]

Function

Rab27 plays a key role in the regulation of exocytosis of vesicles in various cellular organelles. [4] Rab27 uses effectors to tether vesicles to itself and transport them to the plasma membrane, where they undergo fusion. [4] They ensure that vesicles attach correctly, in the proper orientation, at the dedicated site of fusion. However, fusion itself is started when effectors bind SNARE proteins that catalyze the start of exocytosis. [4]

Clinical significance

Mutations

Mutations that prevent the expression of Rab27 ('knock out' mutations) cause the hypopigmentation and immunodeficiency disorder known as type II Griscelli syndrome, while a decrease in Rab27 prenylation is thought to be involved in choroideremia.

The symptoms of type II Griscelli syndrome have shown that Rab27 is involved in melanosome transport in melanocytes and in cytotoxic killing activity in cytotoxic T lymphoblasts. In melanocytes Rab27 binds the melanosome. The melanosome is transported along the microtubule. Rab27 then recruits Slac2A and myosin Va, these enzymes are essential for the transfer of the melanosomes from the microtubules to actin filaments. The melanosomes can now continue on their path towards the cell periphery. If either Rab27, Slac2A or myosin Va are absent then the melanosomes remain in the perinuclear region of the cell. This disruption in pigmentation results in the hypopigmentation seen in the silvery hair colour of patients with Griscelli syndrome.

Cancer

The Rab27a isoform might play a role in cancer. It contributes to the growth of cancerous tumors due to its promotion of chemokine and metalloproteinase secretions. [5] Because of the over-expression of Rab27a in tissues in the breasts, lungs, and pancreas, there may be a linkage between Rab27a presence and likelihood of cancer. [5] Additionally, the release of metalloproteinases results in the breakdown of the ECM, which releases many of the growth factors held within. [6]

References

  1. 1 2 Hou Y, Chen X, Williams SA (2015-04-24). "Rab27". Pancreapedia: The Exocrine Pancreas Knowledge Base. doi: 10.3998/panc.2015.12 .
  2. ↑ Alzahofi N, Welz T, Robinson CL, Page EL, Briggs DA, Stainthorp AK, et al. (2020-07-13). "Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins". Nature Communications. 11 (1): 3495. Bibcode:2020NatCo..11.3495A. doi:10.1038/s41467-020-17212-6. ISSN   2041-1723. PMC   7359353 . PMID   32661310.
  3. ↑ Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. (2009-12-06). "Rab27a and Rab27b control different steps of the exosome secretion pathway". Nature Cell Biology. 12 (1): 19–30, sup pp 1–13. doi:10.1038/ncb2000. hdl: 10044/1/19574 . ISSN   1465-7392. PMID   19966785.
  4. 1 2 3 Izumi T (2021). "In vivo Roles of Rab27 and Its Effectors in Exocytosis". Cell Structure and Function. 46 (2): 79–94. doi:10.1247/csf.21043. ISSN   0386-7196. PMC   10511049 . PMID   34483204.
  5. 1 2 Jamshidiha M, Lanyon-Hogg T, Sutherell CL, Craven GB, Tersa M, De Vita E, et al. (2022). "Identification of the first structurally validated covalent ligands of the small GTPase RAB27A". RSC Medicinal Chemistry. 13 (2): 150–155. doi:10.1039/d1md00225b. ISSN   2632-8682. PMC   8864489 . PMID   35308027.
  6. ↑ Egeblad M, Werb Z (March 2002). "New functions for the matrix metalloproteinases in cancer progression". Nature Reviews. Cancer. 2 (3): 161–174. doi:10.1038/nrc745. ISSN   1474-175X. PMID   11990853.


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