Structural basis of paralog-specific KDM2A/B nucleosome recognition

Cathy J. Spangler; Aleksandra Skrajna; Caroline A. Foley; Anh Nguyen; Gabrielle R. Budziszewski; Dalal N. Azzam; Eyla C. Arteaga; Holly C. Simmons; Charlotte B. Smith; Nathaniel A. Wesley; Emily M. Wilkerson; Jeanne Marie E. McPherson; Dmitri Kireev; Lindsey I. James; Stephen V. Frye; Dennis Goldfarb; Robert K. McGinty

doi:10.1038/s41589-023-01256-y

Structural basis of paralog-specific KDM2A/B nucleosome recognition

Cathy J. Spangler, Aleksandra Skrajna, Caroline A. Foley, Anh Nguyen, Gabrielle R. Budziszewski, Dalal N. Azzam, Eyla C. Arteaga, Holly C. Simmons, Charlotte B. Smith, Nathaniel A. Wesley, Emily M. Wilkerson, Jeanne Marie E. McPherson, Dmitri Kireev, Lindsey I. James, Stephen V. Frye, Dennis Goldfarb, Robert K. McGinty

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Abstract

The nucleosome acidic patch is a major interaction hub for chromatin, providing a platform for enzymes to dock and orient for nucleosome-targeted activities. To define the molecular basis of acidic patch recognition proteome wide, we performed an amino acid resolution acidic patch interactome screen. We discovered that the histone H3 lysine 36 (H3K36) demethylase KDM2A, but not its closely related paralog, KDM2B, requires the acidic patch for nucleosome binding. Despite fundamental roles in transcriptional repression in health and disease, the molecular mechanisms governing nucleosome substrate specificity of KDM2A/B, or any related JumonjiC (JmjC) domain lysine demethylase, remain unclear. We used a covalent conjugate between H3K36 and a demethylase inhibitor to solve cryogenic electron microscopy structures of KDM2A and KDM2B trapped in action on a nucleosome substrate. Our structures show that KDM2–nucleosome binding is paralog specific and facilitated by dynamic nucleosomal DNA unwrapping and histone charge shielding that mobilize the H3K36 sequence for demethylation. [Figure not available: see fulltext.].

Original language	English
Pages (from-to)	624-632
Number of pages	9
Journal	Nature Chemical Biology
Volume	19
Issue number	5
DOIs	https://doi.org/10.1038/s41589-023-01256-y
State	Published - May 2023

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Spangler, C. J., Skrajna, A., Foley, C. A., Nguyen, A., Budziszewski, G. R., Azzam, D. N., Arteaga, E. C., Simmons, H. C., Smith, C. B., Wesley, N. A., Wilkerson, E. M., McPherson, J. M. E., Kireev, D., James, L. I., Frye, S. V., Goldfarb, D., & McGinty, R. K. (2023). Structural basis of paralog-specific KDM2A/B nucleosome recognition. Nature Chemical Biology, 19(5), 624-632. https://doi.org/10.1038/s41589-023-01256-y

@article{0332a196e9804ecab88e6794daf90c2a,

title = "Structural basis of paralog-specific KDM2A/B nucleosome recognition",

abstract = "The nucleosome acidic patch is a major interaction hub for chromatin, providing a platform for enzymes to dock and orient for nucleosome-targeted activities. To define the molecular basis of acidic patch recognition proteome wide, we performed an amino acid resolution acidic patch interactome screen. We discovered that the histone H3 lysine 36 (H3K36) demethylase KDM2A, but not its closely related paralog, KDM2B, requires the acidic patch for nucleosome binding. Despite fundamental roles in transcriptional repression in health and disease, the molecular mechanisms governing nucleosome substrate specificity of KDM2A/B, or any related JumonjiC (JmjC) domain lysine demethylase, remain unclear. We used a covalent conjugate between H3K36 and a demethylase inhibitor to solve cryogenic electron microscopy structures of KDM2A and KDM2B trapped in action on a nucleosome substrate. Our structures show that KDM2–nucleosome binding is paralog specific and facilitated by dynamic nucleosomal DNA unwrapping and histone charge shielding that mobilize the H3K36 sequence for demethylation. [Figure not available: see fulltext.].",

author = "Spangler, {Cathy J.} and Aleksandra Skrajna and Foley, {Caroline A.} and Anh Nguyen and Budziszewski, {Gabrielle R.} and Azzam, {Dalal N.} and Arteaga, {Eyla C.} and Simmons, {Holly C.} and Smith, {Charlotte B.} and Wesley, {Nathaniel A.} and Wilkerson, {Emily M.} and McPherson, {Jeanne Marie E.} and Dmitri Kireev and James, {Lindsey I.} and Frye, {Stephen V.} and Dennis Goldfarb and McGinty, {Robert K.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = may,

doi = "10.1038/s41589-023-01256-y",

language = "English",

volume = "19",

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Spangler, CJ, Skrajna, A, Foley, CA, Nguyen, A, Budziszewski, GR, Azzam, DN, Arteaga, EC, Simmons, HC, Smith, CB, Wesley, NA, Wilkerson, EM, McPherson, JME, Kireev, D, James, LI, Frye, SV, Goldfarb, D & McGinty, RK 2023, 'Structural basis of paralog-specific KDM2A/B nucleosome recognition', Nature Chemical Biology, vol. 19, no. 5, pp. 624-632. https://doi.org/10.1038/s41589-023-01256-y

TY - JOUR

T1 - Structural basis of paralog-specific KDM2A/B nucleosome recognition

AU - Spangler, Cathy J.

AU - Skrajna, Aleksandra

AU - Foley, Caroline A.

AU - Nguyen, Anh

AU - Budziszewski, Gabrielle R.

AU - Azzam, Dalal N.

AU - Arteaga, Eyla C.

AU - Simmons, Holly C.

AU - Smith, Charlotte B.

AU - Wesley, Nathaniel A.

AU - Wilkerson, Emily M.

AU - McPherson, Jeanne Marie E.

AU - Kireev, Dmitri

AU - James, Lindsey I.

AU - Frye, Stephen V.

AU - Goldfarb, Dennis

AU - McGinty, Robert K.

PY - 2023/5

Y1 - 2023/5

N2 - The nucleosome acidic patch is a major interaction hub for chromatin, providing a platform for enzymes to dock and orient for nucleosome-targeted activities. To define the molecular basis of acidic patch recognition proteome wide, we performed an amino acid resolution acidic patch interactome screen. We discovered that the histone H3 lysine 36 (H3K36) demethylase KDM2A, but not its closely related paralog, KDM2B, requires the acidic patch for nucleosome binding. Despite fundamental roles in transcriptional repression in health and disease, the molecular mechanisms governing nucleosome substrate specificity of KDM2A/B, or any related JumonjiC (JmjC) domain lysine demethylase, remain unclear. We used a covalent conjugate between H3K36 and a demethylase inhibitor to solve cryogenic electron microscopy structures of KDM2A and KDM2B trapped in action on a nucleosome substrate. Our structures show that KDM2–nucleosome binding is paralog specific and facilitated by dynamic nucleosomal DNA unwrapping and histone charge shielding that mobilize the H3K36 sequence for demethylation. [Figure not available: see fulltext.].

AB - The nucleosome acidic patch is a major interaction hub for chromatin, providing a platform for enzymes to dock and orient for nucleosome-targeted activities. To define the molecular basis of acidic patch recognition proteome wide, we performed an amino acid resolution acidic patch interactome screen. We discovered that the histone H3 lysine 36 (H3K36) demethylase KDM2A, but not its closely related paralog, KDM2B, requires the acidic patch for nucleosome binding. Despite fundamental roles in transcriptional repression in health and disease, the molecular mechanisms governing nucleosome substrate specificity of KDM2A/B, or any related JumonjiC (JmjC) domain lysine demethylase, remain unclear. We used a covalent conjugate between H3K36 and a demethylase inhibitor to solve cryogenic electron microscopy structures of KDM2A and KDM2B trapped in action on a nucleosome substrate. Our structures show that KDM2–nucleosome binding is paralog specific and facilitated by dynamic nucleosomal DNA unwrapping and histone charge shielding that mobilize the H3K36 sequence for demethylation. [Figure not available: see fulltext.].

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U2 - 10.1038/s41589-023-01256-y

DO - 10.1038/s41589-023-01256-y

M3 - Article

C2 - 36797403

AN - SCOPUS:85148098022

SN - 1552-4450

VL - 19

SP - 624

EP - 632

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 5

ER -

Structural basis of paralog-specific KDM2A/B nucleosome recognition

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