TY - JOUR
T1 - Remote Homology between Munc13 MUN Domain and Vesicle Tethering Complexes
AU - Pei, Jimin
AU - Ma, Cong
AU - Rizo-Rey, Jose
AU - Grishin, Nick V
N1 - Funding Information:
We would like to thank Lisa Kinch for critical reading of the manuscript and helpful suggestions. This work was supported in part by National Institutes of Health grants GM67165 (to N.V.G.) and NS37200 (to J.R.) and by Welch foundation grants I1505 (to N.V.G.) and I1304 (to J.R.).
PY - 2009/8/21
Y1 - 2009/8/21
N2 - Most core components of the neurotransmitter release machinery have homologues in other types of intracellular membrane traffic, likely underlying a universal mechanism of intracellular membrane fusion. However, no clear similarity between Munc13s and protein families generally involved in membrane traffic has been reported, despite the essential nature of Munc13s for neurotransmitter release. This crucial function was ascribed to a minimal Munc13 region called the MUN domain, which likely participates in soluble N-ethylmaleimide sensitive factor attachment protein receptor complex (SNARE) assembly and is also found in Ca2+-dependent activator protein for secretion. We have now used comparative sequence and structural analyses to study the structure and evolutionary origin of the MUN domain. We found weak yet significant sequence similarities between the MUN domain and a set of protein subunits from several related vesicle tethering complexes, such as Sec6 from the exocyst complex and Vps53 from the Golgi-associated retrograde protein complex. Such an evolutionary relationship allows structure prediction of the MUN domain and suggests functional similarities between MUN domain-containing proteins and multisubunit tethering complexes such as exocyst, conserved oligomeric Golgi complex, Golgi-associated retrograde protein complex, and Dsl1p. These findings further unify the mechanism of neurotransmitter release with those of other types of intracellular membrane traffic and, in turn, support a role for tethering complexes in soluble N-ethylmaleimide sensitive factor attachment protein receptor complex assembly.
AB - Most core components of the neurotransmitter release machinery have homologues in other types of intracellular membrane traffic, likely underlying a universal mechanism of intracellular membrane fusion. However, no clear similarity between Munc13s and protein families generally involved in membrane traffic has been reported, despite the essential nature of Munc13s for neurotransmitter release. This crucial function was ascribed to a minimal Munc13 region called the MUN domain, which likely participates in soluble N-ethylmaleimide sensitive factor attachment protein receptor complex (SNARE) assembly and is also found in Ca2+-dependent activator protein for secretion. We have now used comparative sequence and structural analyses to study the structure and evolutionary origin of the MUN domain. We found weak yet significant sequence similarities between the MUN domain and a set of protein subunits from several related vesicle tethering complexes, such as Sec6 from the exocyst complex and Vps53 from the Golgi-associated retrograde protein complex. Such an evolutionary relationship allows structure prediction of the MUN domain and suggests functional similarities between MUN domain-containing proteins and multisubunit tethering complexes such as exocyst, conserved oligomeric Golgi complex, Golgi-associated retrograde protein complex, and Dsl1p. These findings further unify the mechanism of neurotransmitter release with those of other types of intracellular membrane traffic and, in turn, support a role for tethering complexes in soluble N-ethylmaleimide sensitive factor attachment protein receptor complex assembly.
KW - CAPS
KW - MUN domain
KW - Munc13
KW - homology inference and structure prediction
KW - multisubunit tethering complexes exocyst, COG, GARP, and Dsl1p complex
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U2 - 10.1016/j.jmb.2009.06.054
DO - 10.1016/j.jmb.2009.06.054
M3 - Article
C2 - 19563813
AN - SCOPUS:67651160303
SN - 0022-2836
VL - 391
SP - 509
EP - 517
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 3
ER -