A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization
Calmodulin (CaM) is a Ca<sup>2+</sup>-sensor that regulates a wide variety of target proteins, many of which interact through short basic helical motifs bearing two hydrophobic ‘anchor’ residues. CaM comprises two globular lobes, each containing a pair of EF-hand Ca<sup>2+</sup&...
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doaj-9cec5698016b4bbeba0bddf148e3cbbe2020-11-25T03:05:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01212751275110.3390/ijms21082751A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates LocalizationBenjamin M.M. Grant0Masahiro Enomoto1Mitsuhiko Ikura2Christopher B. Marshall3Princess Margaret Cancer Centre, University Health Network, 101 College St., Toronto, ON M5G 1L7, CanadaPrincess Margaret Cancer Centre, University Health Network, 101 College St., Toronto, ON M5G 1L7, CanadaPrincess Margaret Cancer Centre, University Health Network, 101 College St., Toronto, ON M5G 1L7, CanadaPrincess Margaret Cancer Centre, University Health Network, 101 College St., Toronto, ON M5G 1L7, CanadaCalmodulin (CaM) is a Ca<sup>2+</sup>-sensor that regulates a wide variety of target proteins, many of which interact through short basic helical motifs bearing two hydrophobic ‘anchor’ residues. CaM comprises two globular lobes, each containing a pair of EF-hand Ca<sup>2+</sup>-binding motifs that form a Ca<sup>2+</sup>-induced hydrophobic pocket that binds an anchor residue. A central flexible linker allows CaM to accommodate diverse targets. Several reported CaM interactors lack these anchors but contain Lys/Arg-rich polybasic sequences adjacent to a lipidated N- or C-terminus. Ca<sup>2+</sup>-CaM binds the myristoylated N-terminus of CAP23/NAP22 with intimate interactions between the lipid and a surface comprised of the hydrophobic pockets of both lobes, while the basic residues make electrostatic interactions with the negatively charged surface of CaM. Ca<sup>2+</sup>-CaM binds farnesylcysteine, derived from the farnesylated polybasic C-terminus of KRAS4b, with the lipid inserted into the C-terminal lobe hydrophobic pocket. CaM sequestration of the KRAS4b farnesyl moiety disrupts KRAS4b membrane association and downstream signaling. Phosphorylation of basic regions of N-/C-terminal lipidated CaM targets can reduce affinity for both CaM and the membrane. Since both N-terminal myristoylated and C-terminal prenylated proteins use a Singly Lipidated Polybasic Terminus (SLIPT) for CaM binding, we propose these polybasic lipopeptide elements comprise a non-canonical CaM-binding motif.https://www.mdpi.com/1422-0067/21/8/2751CalmodulinKRAS4bprenylationmyristoylationpolybasic regionCa2+ signaling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Benjamin M.M. Grant Masahiro Enomoto Mitsuhiko Ikura Christopher B. Marshall |
spellingShingle |
Benjamin M.M. Grant Masahiro Enomoto Mitsuhiko Ikura Christopher B. Marshall A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization International Journal of Molecular Sciences Calmodulin KRAS4b prenylation myristoylation polybasic region Ca2+ signaling |
author_facet |
Benjamin M.M. Grant Masahiro Enomoto Mitsuhiko Ikura Christopher B. Marshall |
author_sort |
Benjamin M.M. Grant |
title |
A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization |
title_short |
A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization |
title_full |
A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization |
title_fullStr |
A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization |
title_full_unstemmed |
A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization |
title_sort |
non-canonical calmodulin target motif comprising a polybasic region and lipidated terminal residue regulates localization |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-04-01 |
description |
Calmodulin (CaM) is a Ca<sup>2+</sup>-sensor that regulates a wide variety of target proteins, many of which interact through short basic helical motifs bearing two hydrophobic ‘anchor’ residues. CaM comprises two globular lobes, each containing a pair of EF-hand Ca<sup>2+</sup>-binding motifs that form a Ca<sup>2+</sup>-induced hydrophobic pocket that binds an anchor residue. A central flexible linker allows CaM to accommodate diverse targets. Several reported CaM interactors lack these anchors but contain Lys/Arg-rich polybasic sequences adjacent to a lipidated N- or C-terminus. Ca<sup>2+</sup>-CaM binds the myristoylated N-terminus of CAP23/NAP22 with intimate interactions between the lipid and a surface comprised of the hydrophobic pockets of both lobes, while the basic residues make electrostatic interactions with the negatively charged surface of CaM. Ca<sup>2+</sup>-CaM binds farnesylcysteine, derived from the farnesylated polybasic C-terminus of KRAS4b, with the lipid inserted into the C-terminal lobe hydrophobic pocket. CaM sequestration of the KRAS4b farnesyl moiety disrupts KRAS4b membrane association and downstream signaling. Phosphorylation of basic regions of N-/C-terminal lipidated CaM targets can reduce affinity for both CaM and the membrane. Since both N-terminal myristoylated and C-terminal prenylated proteins use a Singly Lipidated Polybasic Terminus (SLIPT) for CaM binding, we propose these polybasic lipopeptide elements comprise a non-canonical CaM-binding motif. |
topic |
Calmodulin KRAS4b prenylation myristoylation polybasic region Ca2+ signaling |
url |
https://www.mdpi.com/1422-0067/21/8/2751 |
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