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PDBsum entry 3tpo
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Protein transport
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PDB id
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3tpo
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References listed in PDB file
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Key reference
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Title
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Sensing actin dynamics: structural basis for g-Actin-Sensitive nuclear import of mal.
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Authors
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H.Hirano,
Y.Matsuura.
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Ref.
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Biochem Biophys Res Commun, 2011,
414,
373-378.
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PubMed id
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Abstract
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The coordination of cytoskeletal actin dynamics with gene expression
reprogramming is emerging as a crucial mechanism to control diverse cellular
processes, including cell migration, differentiation and neuronal circuit
assembly. The actin-binding transcriptional coactivator MAL (also known as
MRTF-A/MKL1/BSAC) senses G-actin concentration and transduces Rho GTPase signals
to serum response factor (SRF). MAL rapidly shuttles between the cytoplasm and
the nucleus in unstimulated cells but Rho-induced depletion of G-actin leads to
MAL nuclear accumulation and activation of transcription of SRF:MAL-target
genes. Although the molecular and structural basis of actin-regulated
nucleocytoplasmic shuttling of MAL is not understood fully, it is proposed that
nuclear import of MAL is mediated by importin α/β heterodimer, and that
G-actin competes with importin α/β for the binding to MAL. Here we present
structural, biochemical and cell biological evidence that MAL has a classical
bipartite nuclear localization signal (NLS) in the N-terminal 'RPEL' domain
containing Arg-Pro-X-X-X-Glu-Leu (RPEL) motifs. The NLS residues of MAL adopt an
extended conformation and bind along the surface groove of importin-α,
interacting with the major- and minor-NLS binding sites. We also present a
crystal structure of wild-type MAL RPEL domain in complex with five G-actins.
Comparison of the importin-α- and actin-complexes revealed that the binding of
G-actins to MAL is associated with folding of NLS residues into a helical
conformation that is inappropriate for importin-α recognition.
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