Chemistry Reference
In-Depth Information
previously unknown role in protein biogenesis based on the recruitment of Hsp70
and ribosomes to the ER membrane.
Bag1 has two putative orthologs in the fission yeast
Schizosaccharomyces
pombe
, Bag101/Bag1A and Bag102/Bag1B. Both proteins have an Ubl and a C-ter-
minal BAG domain and associate with the 26S proteasome and Hsp70 respectively.
Interestingly, Bag102 contains an additional N-terminal single transmembrane helix
localizing it to the ER/nuclear membrane, similar to Snl1p. It was recently found
that Bag102 but not Bag101 was able to suppress the temperature-sensitive growth
phenotype and the DNA segregation defect of a
spc7-23
strain, which contains a
point mutation in a conserved kinetochore component Spc7 (Kriegenburg et al.
2014
). This suggests that these two BAG proteins in fission yeast have separate and
specific cellular functions.
The crystal structure of the BAG domain of the
C. elegans
Bag1 homolog re-
vealed a dimeric structure of two protomers forming mixed three-helix bundles
(Symersky et al.
2004
). A small ʲ-sheet between helices 2 and 3 interferes with the
formation of an intramolecular three-helix bundle in this ortholog. However, the
function of this BAG domain protein as well as the putative Bag3 homolog unc-23
remains poorly characterized.
In
D. melanogaster
, the Bag3 homolog starvin was shown to be regulated in
a highly developmental-stage specific manner and is expressed in larval somatic
muscles. The name starvin was coined as this protein was essential for viability and
was required by newly hatched larvae to ingest food and grow (Coulson et al.
2005
).
Starvin expression correlates with the response to cold exposure in
D. melanogas-
ter
, but the precise role of this protein in the pathway is not known (Colinet and
Hoffmann
2010
). It was proposed that it plays a role in modulating Hsp70 chaper-
one activity during recovery, although this will have to be experimentally verified.
Plants contain a large variety of BAG family proteins. Sequences for seven iso-
forms, named AtBAG1-7, have been identified in the
A. thaliana
genome (Kab-
bage and Dickman
2008
). A comparative structural study on the AtBAG1-4 proteins,
which share an architecture consisting of a Ubl and a BAG domain, showed that the
respective BAG domains have short three-helix bundle structures similar to human
Bag3, Bag4 and Bag5 (Fang et al.
2013
). All the proteins lower the binding affinity
of ADP with the NBD to a similar degree, suggesting functional redundancy. The
structure of the complex of AtBAG1 with the NBD of human Hsp70 revealed for
the first time Ubl and BAG domain in context, showing an extended conformation
(Fang et al.
2013
). The NBD conformation was similar to the Bag1 and Bag5 com-
plexes, with the subdomain IIB rotated 15ﾰ away from the nucleotide binding site.
AtBAG2 mutant plants are larger than wildtype counterparts, implicating a function
of this isoform in plant programmed cell death (PCD). Similarly, AtBAG4 confers
tolerance to salt stress, apparently also by inhibiting PCD (Doukhanina et al.
2006
).
AtBAG7 is the only known ER-lumenal BAG domain protein (Williams et al.
2010
).
Thus, in cells the diversity of BAG domain-containing proteins appears to serve
in recruiting Hsp70 to specific locations and for specific functions. How the combi-
natorial assembly with multiple co-chaperones governs the biochemical properties
of Hsp70 will be a fertile field for further studies.
Search WWH ::
Custom Search