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PDBsum entry 4by5
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Calcium-binding protein
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PDB id
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4by5
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References listed in PDB file
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Key reference
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Title
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The guanine-Exchange factor ric8a binds to the ca²⁺ sensor ncs-1 to regulate synapse number and neurotransmitter release.
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Authors
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J.Romero-Pozuelo,
J.S.Dason,
A.Mansilla,
S.Baños-Mateos,
J.L.Sardina,
A.Chaves-Sanjuán,
J.Jurado-Gómez,
E.Santana,
H.L.Atwood,
..Hernández-Hernández,
M.J.Sánchez-Barrena,
A.Ferrús.
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Ref.
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J Cell Sci, 2014,
127,
4246-4259.
[DOI no: ]
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PubMed id
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Abstract
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The conserved Ca(2+)-binding protein Frequenin (homolog of the mammalian NCS-1,
neural calcium sensor) is involved in pathologies that result from abnormal
synapse number and probability of neurotransmitter release per synapse. Both
synaptic features are likely to be co-regulated but the intervening mechanisms
remain poorly understood. We show here that Drosophila Ric8a (a homolog of
mammalian synembryn, which is also known as Ric8a), a receptor-independent
activator of G protein complexes, binds to Frq2 but not to the virtually
identical homolog Frq1. Based on crystallographic data on Frq2 and site-directed
mutagenesis on Frq1, the differential amino acids R94 and T138 account for this
specificity. Human NCS-1 and Ric8a reproduce the binding and maintain the
structural requirements at these key positions. Drosophila Ric8a and Gαs
regulate synapse number and neurotransmitter release, and both are functionally
linked to Frq2. Frq2 negatively regulates Ric8a to control synapse number.
However, the regulation of neurotransmitter release by Ric8a is independent of
Frq2 binding. Thus, the antagonistic regulation of these two synaptic properties
shares a common pathway, Frq2-Ric8a-Gαs, which diverges downstream. These
mechanisms expose the Frq2-Ric8a interacting surface as a potential
pharmacological target for NCS-1-related diseases and provide key data towards
the corresponding drug design.
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