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Allosteric control of the exportin CRM1 unraveled by crystal structure analysis.

Monecke T, Dickmanns A, Ficner R - FEBS J. (2014)

Bottom Line: Moreover, during the last decade, CRM1 has become a more and more appreciated target for anti-cancer drugs.Hence, detailed understanding of the flexibility, the regulatory features and the positive binding cooperativity between CRM1, Ran and cargo is a prerequisite for the development of highly effective drugs.Here we review recent structural advances in the characterization of CRM1 and CRM1-containing complexes with a special emphasis on X-ray crystallographic studies.

View Article: PubMed Central - PubMed

Affiliation: Abteilung für Molekulare Strukturbiologie, Institut für Mikrobiologie und Genetik, Göttinger Zentrum für Molekulare Biowissenschaften, Georg-August-Universität Göttingen, Germany.

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HEAT-repeat architecture and overall structure of CRM1. (A) Structural organization of a HEAT repeat composed of two consecutive anti-parallel helices connected by a short linker loop. Commonly, the A-helix (red) is located at the outer, convex surface and the B-helix (yellow) lines the inner, concave area. HEAT repeats are characterized by pronounced intra-HEAT-repeat hydrophobic interactions. (B) CRM1 consists of an array of 21 consecutive HEAT repeats (H1–H21) forming an overall superhelical and flexible molecule. The acidic loop (green), NES cleft and the C-terminal helix with the adjacent C-terminal acidic tail are structural key features crucial for CRM1 function.
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fig02: HEAT-repeat architecture and overall structure of CRM1. (A) Structural organization of a HEAT repeat composed of two consecutive anti-parallel helices connected by a short linker loop. Commonly, the A-helix (red) is located at the outer, convex surface and the B-helix (yellow) lines the inner, concave area. HEAT repeats are characterized by pronounced intra-HEAT-repeat hydrophobic interactions. (B) CRM1 consists of an array of 21 consecutive HEAT repeats (H1–H21) forming an overall superhelical and flexible molecule. The acidic loop (green), NES cleft and the C-terminal helix with the adjacent C-terminal acidic tail are structural key features crucial for CRM1 function.

Mentions: Generally, importin β type nuclear transport receptors are composed of a varying number of HEAT repeats. The canonical HEAT repeat is a structural motif formed by two anti-parallel helices (named A- and B-helix) connected by a short linker loop and a typical total length of ∼ 40–50 residues (Fig.2A) 77,78. They have been named after the first couple of proteins bearing this motif, namely huntingtin, elongation factor 3 (EF3), the regulatory A subunit of protein phosphatase 2A (PP2A) and the P3 kinase TOR1.


Allosteric control of the exportin CRM1 unraveled by crystal structure analysis.

Monecke T, Dickmanns A, Ficner R - FEBS J. (2014)

HEAT-repeat architecture and overall structure of CRM1. (A) Structural organization of a HEAT repeat composed of two consecutive anti-parallel helices connected by a short linker loop. Commonly, the A-helix (red) is located at the outer, convex surface and the B-helix (yellow) lines the inner, concave area. HEAT repeats are characterized by pronounced intra-HEAT-repeat hydrophobic interactions. (B) CRM1 consists of an array of 21 consecutive HEAT repeats (H1–H21) forming an overall superhelical and flexible molecule. The acidic loop (green), NES cleft and the C-terminal helix with the adjacent C-terminal acidic tail are structural key features crucial for CRM1 function.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231977&req=5

fig02: HEAT-repeat architecture and overall structure of CRM1. (A) Structural organization of a HEAT repeat composed of two consecutive anti-parallel helices connected by a short linker loop. Commonly, the A-helix (red) is located at the outer, convex surface and the B-helix (yellow) lines the inner, concave area. HEAT repeats are characterized by pronounced intra-HEAT-repeat hydrophobic interactions. (B) CRM1 consists of an array of 21 consecutive HEAT repeats (H1–H21) forming an overall superhelical and flexible molecule. The acidic loop (green), NES cleft and the C-terminal helix with the adjacent C-terminal acidic tail are structural key features crucial for CRM1 function.
Mentions: Generally, importin β type nuclear transport receptors are composed of a varying number of HEAT repeats. The canonical HEAT repeat is a structural motif formed by two anti-parallel helices (named A- and B-helix) connected by a short linker loop and a typical total length of ∼ 40–50 residues (Fig.2A) 77,78. They have been named after the first couple of proteins bearing this motif, namely huntingtin, elongation factor 3 (EF3), the regulatory A subunit of protein phosphatase 2A (PP2A) and the P3 kinase TOR1.

Bottom Line: Moreover, during the last decade, CRM1 has become a more and more appreciated target for anti-cancer drugs.Hence, detailed understanding of the flexibility, the regulatory features and the positive binding cooperativity between CRM1, Ran and cargo is a prerequisite for the development of highly effective drugs.Here we review recent structural advances in the characterization of CRM1 and CRM1-containing complexes with a special emphasis on X-ray crystallographic studies.

View Article: PubMed Central - PubMed

Affiliation: Abteilung für Molekulare Strukturbiologie, Institut für Mikrobiologie und Genetik, Göttinger Zentrum für Molekulare Biowissenschaften, Georg-August-Universität Göttingen, Germany.

Show MeSH
Related in: MedlinePlus