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The Differential Response to Ca2+ from Vertebrate and Invertebrate Calumenin Is Governed by a Single Amino Acid Residue
journal contribution
posted on 2018-01-10, 00:00 authored by Sasirekha Narayanasamy, Gopala Krishna AradhyamCalumenin
(Calu) is a well-conserved multi-EF-hand-containing Ca2+-binding protein. In this work, we focused on the alterations
that calumenin has undergone during evolution. We demonstrate that
vertebrate calumenin is significantly different from its invertebrate
homologues with respect to its response to Ca2+ binding.
Human calumenin (HsCalu1) is intrinsically unstructured in the Ca2+ free form and responds to Ca2+ with a dramatic
gain in structure. Calumenin from Caenorhabditis elegans (CeCalu) is structured even in the apo form, with no conformational
change upon binding of Ca2+. We decode this structural
and functional distinction by identifying a single “Leu”
residue-based switch located in the fourth EF-hand of HsCalu1, occupied
by “Gly” in the invertebrate homologues. We demonstrate
that replacing Leu with Gly (L150G) in HsCalu1 enables the protein
to adopt a structural fold even in the Ca2+ free form,
similar to CeCalu, leading to ligand compensation (adoption of structure
in the absence of Ca2+). The fourth (of seven) EF-hand
of HsCalu1 nucleates the structural fold of the protein depending
on the switch residue (Gly or Leu). Our analyses reveal that the Leu
that replaced Gly from fishes onward is absolutely conserved in higher
vertebrates, while lower organisms have Gly, not only enlarging the
scope of Ca2+-dependent structural transitions but also
drawing a boundary between the invertebrate and vertebrate calumenin.
The evolutionary selection of the switch residue strongly corroborates
the change in the structure of the protein and its pleiotropic functions
and seems like it can be extended to the presence or absence of a
heart in that organism.