7epu

Crystal structure of HsALC1Crystal structure of HsALC1

Structural highlights

7epu is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.5Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CHD1L_HUMAN ATP-dependent chromatin remodeler that mediates chromatin-remodeling following DNA damage (PubMed:19661379, PubMed:29220652, PubMed:29220653, PubMed:33357431, PubMed:34486521, PubMed:34874266, PubMed:34210977). Recruited to DNA damage sites through interaction with poly-ADP-ribose: specifically recognizes and binds histones that are poly-ADP-ribosylated on serine residues in response to DNA damage (PubMed:19661379, PubMed:29220652, PubMed:29220653, PubMed:34874266, PubMed:34486521). Poly-ADP-ribose-binding activates the ATP-dependent chromatin remodeler activity, thereby regulating chromatin during DNA repair (PubMed:19661379, PubMed:29220652, PubMed:29220653, PubMed:34874266, PubMed:34486521). Catalyzes nucleosome sliding away from DNA breaks in an ATP-dependent manner (PubMed:19661379, PubMed:29220652, PubMed:29220653). Chromatin remodeling activity promotes PARP2 removal from chromatin (PubMed:33275888).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Chromatin remodeler ALC1 (amplification in liver cancer 1) is crucial for repairing damaged DNA. It is autoinhibited and activated by nucleosomal epitopes. However, the mechanisms by which ALC1 is regulated remain unclear. Here we report the crystal structure of human ALC1 and the cryoEM structure bound to the nucleosome. The structure shows the macro domain of ALC1 binds to lobe 2 of the ATPase motor, sequestering two elements for nucleosome recognition, explaining the autoinhibition mechanism of the enzyme. The H4 tail competes with the macro domain for lobe 2-binding, explaining the requirement for this nucleosomal epitope for ALC1 activation. A dual-arginine-anchor motif of ALC1 recognizes the acidic pocket of the nucleosome, which is critical for chromatin remodeling in vitro. Together, our findings illustrate the structures of ALC1 and shed light on its regulation mechanisms, paving the way for the discovery of drugs targeting ALC1 for the treatment of cancer.

Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome.,Wang L, Chen K, Chen Z Nat Commun. 2021 Jul 1;12(1):4057. doi: 10.1038/s41467-021-24320-4. PMID:34210977^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ahel D, Horejsi Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I, Flynn H, Skehel M, West SC, Jackson SP, Owen-Hughes T, Boulton SJ. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science. 2009 Sep 4;325(5945):1240-3. doi: 10.1126/science.1177321. Epub 2009 Aug, 6. PMID:19661379 doi:10.1126/science.1177321
↑ Lehmann LC, Hewitt G, Aibara S, Leitner A, Marklund E, Maslen SL, Maturi V, Chen Y, van der Spoel D, Skehel JM, Moustakas A, Boulton SJ, Deindl S. Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1. Mol Cell. 2017 Dec 7;68(5):847-859.e7. PMID:29220652 doi:10.1016/j.molcel.2017.10.017
↑ Singh HR, Nardozza AP, Möller IR, Knobloch G, Kistemaker HAV, Hassler M, Harrer N, Blessing C, Eustermann S, Kotthoff C, Huet S, Mueller-Planitz F, Filippov DV, Timinszky G, Rand KD, Ladurner AG. A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene. Mol Cell. 2017 Dec 7;68(5):860-871.e7. PMID:29220653 doi:10.1016/j.molcel.2017.11.019
↑ Blessing C, Mandemaker IK, Gonzalez-Leal C, Preisser J, Schomburg A, Ladurner AG. The Oncogenic Helicase ALC1 Regulates PARP Inhibitor Potency by Trapping PARP2 at DNA Breaks. Mol Cell. 2020 Dec 3;80(5):862-875.e6. PMID:33275888 doi:10.1016/j.molcel.2020.10.009
↑ Lehmann LC, Bacic L, Hewitt G, Brackmann K, Sabantsev A, Gaullier G, Pytharopoulou S, Degliesposti G, Okkenhaug H, Tan S, Costa A, Skehel JM, Boulton SJ, Deindl S. Mechanistic Insights into Regulation of the ALC1 Remodeler by the Nucleosome Acidic Patch. Cell Rep. 2020 Dec 22;33(12):108529. PMID:33357431 doi:10.1016/j.celrep.2020.108529
↑ Wang L, Chen K, Chen Z. Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome. Nat Commun. 2021 Jul 1;12(1):4057. PMID:34210977 doi:10.1038/s41467-021-24320-4
↑ Bacic L, Gaullier G, Sabantsev A, Lehmann LC, Brackmann K, Dimakou D, Halic M, Hewitt G, Boulton SJ, Deindl S. Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome. Elife. 2021 Sep 6;10:e71420. PMID:34486521 doi:10.7554/eLife.71420
↑ Mohapatra J, Tashiro K, Beckner RL, Sierra J, Kilgore JA, Williams NS, Liszczak G. Serine ADP-ribosylation marks nucleosomes for ALC1-dependent chromatin remodeling. Elife. 2021 Dec 7;10:e71502. PMID:34874266 doi:10.7554/eLife.71502
↑ Wang L, Chen K, Chen Z. Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome. Nat Commun. 2021 Jul 1;12(1):4057. PMID:34210977 doi:10.1038/s41467-021-24320-4

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OCA

[1] Ahel D, Horejsi Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I, Flynn H, Skehel M, West SC, Jackson SP, Owen-Hughes T, Boulton SJ. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science. 2009 Sep 4;325(5945):1240-3. doi: 10.1126/science.1177321. Epub 2009 Aug, 6. PMID:19661379 doi:10.1126/science.1177321

[2] Lehmann LC, Hewitt G, Aibara S, Leitner A, Marklund E, Maslen SL, Maturi V, Chen Y, van der Spoel D, Skehel JM, Moustakas A, Boulton SJ, Deindl S. Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1. Mol Cell. 2017 Dec 7;68(5):847-859.e7. PMID:29220652 doi:10.1016/j.molcel.2017.10.017

[3] Singh HR, Nardozza AP, Möller IR, Knobloch G, Kistemaker HAV, Hassler M, Harrer N, Blessing C, Eustermann S, Kotthoff C, Huet S, Mueller-Planitz F, Filippov DV, Timinszky G, Rand KD, Ladurner AG. A Poly-ADP-Ribose Trigger Releases the Auto-Inhibition of a Chromatin Remodeling Oncogene. Mol Cell. 2017 Dec 7;68(5):860-871.e7. PMID:29220653 doi:10.1016/j.molcel.2017.11.019

[4] Blessing C, Mandemaker IK, Gonzalez-Leal C, Preisser J, Schomburg A, Ladurner AG. The Oncogenic Helicase ALC1 Regulates PARP Inhibitor Potency by Trapping PARP2 at DNA Breaks. Mol Cell. 2020 Dec 3;80(5):862-875.e6. PMID:33275888 doi:10.1016/j.molcel.2020.10.009

[5] Lehmann LC, Bacic L, Hewitt G, Brackmann K, Sabantsev A, Gaullier G, Pytharopoulou S, Degliesposti G, Okkenhaug H, Tan S, Costa A, Skehel JM, Boulton SJ, Deindl S. Mechanistic Insights into Regulation of the ALC1 Remodeler by the Nucleosome Acidic Patch. Cell Rep. 2020 Dec 22;33(12):108529. PMID:33357431 doi:10.1016/j.celrep.2020.108529

[6] Wang L, Chen K, Chen Z. Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome. Nat Commun. 2021 Jul 1;12(1):4057. PMID:34210977 doi:10.1038/s41467-021-24320-4

[7] Bacic L, Gaullier G, Sabantsev A, Lehmann LC, Brackmann K, Dimakou D, Halic M, Hewitt G, Boulton SJ, Deindl S. Structure and dynamics of the chromatin remodeler ALC1 bound to a PARylated nucleosome. Elife. 2021 Sep 6;10:e71420. PMID:34486521 doi:10.7554/eLife.71420

[8] Mohapatra J, Tashiro K, Beckner RL, Sierra J, Kilgore JA, Williams NS, Liszczak G. Serine ADP-ribosylation marks nucleosomes for ALC1-dependent chromatin remodeling. Elife. 2021 Dec 7;10:e71502. PMID:34874266 doi:10.7554/eLife.71502

[9] Wang L, Chen K, Chen Z. Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome. Nat Commun. 2021 Jul 1;12(1):4057. PMID:34210977 doi:10.1038/s41467-021-24320-4

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