Biomedical Engineering Reference
In-Depth Information
Bet3
Bet5
Trs23
Bet3 C-terminal
extension with
aspartate finger
Ypt (Rab1)
Fig. 5.2 The TRAPP longin core domains and Bet3 aspartate finger subunit. The polypeptide
backbones of the Bet5 (
green
) and Trs23 (
magenta
) longin domain core subunits of TRAPP are
shown in ribbon form. The longin domain is formed by two alpha-helices that form a hairpin
overlaid by 5 beta-sheets. The final long alpha-helix lies over this platform and forms the
interaction with the adjacent longin subunit which is related by a 180
rotation. The target Rab,
Ypt1, sits on top of this platform slightly offset towards Trs23. The Bet3 subunit (
cyan
) contributes
an extended C-terminal region carrying the aspartate finger residue needed for GEF activity
does not result in a reduction in either TRAPP- or DrrA-mediated GDP-release
(Langemeyer et al.
2014
). The defining feature of the Rab1-DrrA complex therefore
appears to be a ternary interaction involving the Rab P-loop lysine 21 and switch II
aspartate 63 and glutamine 67. Mutational analysis indicates that glutamine
67 although not required for nucleotide binding is important for DrrA-stimulated
GDP release. This mutation has no effect on TRAPP-stimulated GDP release
consistent with the structural data suggesting that the P-loop lysine interacts with
the aspartate finger residue in the Bet3 C-terminus (Cai et al.
2008
). DrrA and
TRAPP therefore promote different conformations in Rab1, both of which lead to
GDP release. This indicates there is considerable plasticity in the Rab nucleotide-
binding domain, and that Rab GEFs can promote exchange by mechanistically
separable pathways (Langemeyer et al.
2014
).
5.2.5 DENN and DENN-Related Proteins Act
on Diverse Rabs
DENN (differentially expressed normal versus neoplastic) domain proteins form
the largest group of Rab GEFs (Levivier et al.
2001
; Marat et al.
2011
; Sato
et al.
2008
; Allaire et al.
2010
; Yoshimura et al.
2010
). In humans this family
comprises seven subgroups DENND1-5, myotubularin-related proteins 5 and
13 (MTMR5/13) and MAP-kinase activating death domain protein (MADD), and
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