Rab Escort Protein 1: a multi-mediator of intracellular

components and an important protein to humans

Fernandes, N. C. F; Baia, V. P.
School of Pharmacy and Molecular Science

Rab Escort Protein 1 (REP1)

Rab proteins direct the vesicle to specific spots on the
correct
target
membrane.
Therefore,
as
a
multifunctional regulator of the Rab proteins, REP 1 is
an important mediator of intracellular interactions to
ensure an orderly flow of vesicular traffic. 1,2

Structure and function

REP1 contains a large cylindrical domain I consisting
of four sheets and six helixes and a smaller domain II
composed of five helices.2
Rab proteins subfamily1
REP1 is a X-linked gene of 15 exons predicting a
2
protein of 653 amino acids.
REP1:RabGGTase complex3

Figure 1 REP 1 gene.2

REP1 is an X-linked
gene. Mutations in the
human REP1 gene result
in Choroideremia, an Xlinked
progressive
retinal
degeneration
(Xq21.2).

Figure 2 Structure of REP 1 and of the REP1:RabGGTase complex.3 (A and B) Domain I of REP-1 is
shown as a blue ribbon, while domain II is displayed
in light blue, the Rab-binding platform in red, the Cterminal binding region (CBR) in pale orange and the
mobile effector loop (MEL) in green. The partially
obscured pink sphere adjacent to the isoprenoid
group is the catalytic zinc ion. The -helical region of
the -subunit of RabGGTase is in orange, while the
-subunit is shown in yellow, the Ig-like domain in
magenta and the LRR (leucine-rich repeat) in gray.

Carrier proteins of escorting 3, 4, 5

- Rab geranylation - geranyl-geranyl transferase 2
(GGTase2)
- Rab targeting - GTP dissociation inhibitor (GDI)

Role in cell regulation process

Chromoideremia
Gene (CHM) can modify the REP 1 protein function or
even the abolish of REP 1 protein production;
Less production or the absence of the REP 1 in the
cell;
Progressive degeneration of photoreceptors;
Retinal pigment epithelium:
Choriocapillaris (Figure 5);
This disease is X-linked recessive, commonly affects
males, and it is rarer in carried females (referencia com
a vanessa).
Symptoms of Choroideremia: night blindness,
progressive visual field restriction and often blindness.
Some patients present good central vision until age 4050 years (referencia com a vanessa).

Figure 5: The first picture represents an 18 years old CHM affected man showing asymmetrical
profound chorioretinal atrophy with preservation of central macula. The second picture
represents a normal eye (referencia no fim).

Gene therapy for patients with

Choroideremia
Recent studies have tested the effects of retinal gene
therapy with an adeno-associated viral vector encoding
REP 1 in patients with Choroideremia. The study has as
objective to deliver CHM gene into the cells of retina,
in an operation similar to cataract surgery, to start
producing REP 1 and stop the cells dying off. The results
showing improvement in vision in the first six patients
confirm that the virus can deliver its DNA payload
without causing significant damage to the retina. This
has huge implications for anyone with a genetic retinal
disease.

References

Figure 3 Rab geranylation (1) and targeting (2) using REP1 as co-factor for
GGTase2.5 Nascent Rab proteins are taken from the endoplasmic reticulum (ER)
and presented to GGTase2 for geranyl-geranyl modication REP1. Moreover,
REP1 acts as a GTP dissociation inhibitor (GDI) until the Rab protein is guided
to its target compartment and membrane acceptor to start the rst cycle of
activity. Rabs are used to target ER-microsomes (M) to the Golgi apparatus (GA)
(2), controlled budding and fusion of Golgi vesicles (3), budding of secretory
vesicles (sV) (4), fusion of lysosomes (L) and endosomes (5) as well as
endosome budding (E) (6). After delivering the Rab proteins to their rst
target, REP1 dissociates and re-enters another cycle of RAB geranylation and
targeting.
RESEARCH POSTER PRESENTATION DESIGN 2012

www.PosterPresentations.com

1. Alberts B, Johnson A, Lewis J, Raff M, et al. Molecular Biology of the Cell. 5th ed. New York, United States: Garland
science, Taylor & Francis Group (pp. 760-762); 2008.
2. Andres DA, Seabra MC, Brown MS, Armstrong SA, Smeland TE, et al. cDNA cloning of component A of Rab
geranylgeranyl transferase and demonstration of its role as a Rab escort protein. Cell. 1993; 73: 1091-1099.
3. Goody RS, Rak A, Alexandrov K. The structural and mechanistic basis for recycling of Rab proteins between membrane
compartments. CMLS, Cell. Mol. Life Sci. 2005; 62: 16571670.
4. Pereira-Leal JB, Strom M, Godfrey RF, Seabraat MC. Structural determinants of Rab and Rab Escort Protein
interaction: Rab family motifs dene a conserved binding surface. Biochemical and Biophysical Research
Communications. 2003; 301: 9297 2003.
5. Preising MN, Ayuso C. Rab escort protein 1 (REP1) in intracellular trafc: a functional and pathophysiological
overview. Ophthalmic Genetics. 2004; Vol. 25 No. 2, pp. 101110.
CHM. Genetics Home Reference. http://ghr.nlm.nih.gov/gene/CHM. Published July, 2013. Reviewed August 18, 2014.
Accessed August 20, 2014.
MacLaren, R. E.; Groppe, M.; Barnard, A. R. et al. Retinal gene therapy in patients with choroideremia: initial findings
from a phase 1/2 clinical trial. Lancet. (2014) 29;383 (9923):1129-37. doi: 10.1016/S0140-6736(13)62117-0.
MacDonald, I. M.; Russell, L.; Chan, C. C. Choroideremia: New Findings from Ocular Pathology and Review of Recent
Literature. Surv Ophthalmol, 54 (3), May--June 2009. doi:10.1016/j.survophthal.2009.02.008