TY - JOUR
T1 - Glutamylation of Npm2 and Nap1 acidic disordered regions increases DNA mimicry and histone chaperone efficiency
AU - Lorton, Benjamin M.
AU - Warren, Christopher
AU - Ilyas, Humaira
AU - Nandigrami, Prithviraj
AU - Hegde, Subray
AU - Cahill, Sean
AU - Lehman, Stephanie M.
AU - Shabanowitz, Jeffrey
AU - Hunt, Donald F.
AU - Fiser, Andras
AU - Cowburn, David
AU - Shechter, David
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/4/19
Y1 - 2024/4/19
N2 - Histone chaperones–structurally diverse, non-catalytic proteins enriched with acidic intrinsically disordered regions (IDRs)–protect histones from spurious nucleic acid interactions and guide their deposition into and out of nucleosomes. Despite their conservation and ubiquity, the function of the chaperone acidic IDRs remains unclear. Here, we show that the Xenopus laevis Npm2 and Nap1 acidic IDRs are substrates for TTLL4 (Tubulin Tyrosine Ligase Like 4)-catalyzed post-translational glutamate-glutamylation. We demonstrate that to bind, stabilize, and deposit histones into nucleosomes, chaperone acidic IDRs function as DNA mimetics. Our biochemical, computational, and biophysical studies reveal that glutamylation of these chaperone polyelectrolyte acidic stretches functions to enhance DNA electrostatic mimicry, promoting the binding and stabilization of H2A/H2B heterodimers and facilitating nucleosome assembly. This discovery provides insights into both the previously unclear function of the acidic IDRs and the regulatory role of post-translational modifications in chromatin dynamics.
AB - Histone chaperones–structurally diverse, non-catalytic proteins enriched with acidic intrinsically disordered regions (IDRs)–protect histones from spurious nucleic acid interactions and guide their deposition into and out of nucleosomes. Despite their conservation and ubiquity, the function of the chaperone acidic IDRs remains unclear. Here, we show that the Xenopus laevis Npm2 and Nap1 acidic IDRs are substrates for TTLL4 (Tubulin Tyrosine Ligase Like 4)-catalyzed post-translational glutamate-glutamylation. We demonstrate that to bind, stabilize, and deposit histones into nucleosomes, chaperone acidic IDRs function as DNA mimetics. Our biochemical, computational, and biophysical studies reveal that glutamylation of these chaperone polyelectrolyte acidic stretches functions to enhance DNA electrostatic mimicry, promoting the binding and stabilization of H2A/H2B heterodimers and facilitating nucleosome assembly. This discovery provides insights into both the previously unclear function of the acidic IDRs and the regulatory role of post-translational modifications in chromatin dynamics.
KW - Biological sciences
KW - Molecular biology
KW - Protein structure aspects
KW - Structural biology
UR - http://www.scopus.com/inward/record.url?scp=85188708187&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85188708187&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.109458
DO - 10.1016/j.isci.2024.109458
M3 - Article
AN - SCOPUS:85188708187
SN - 2589-0042
VL - 27
JO - iScience
JF - iScience
IS - 4
M1 - 109458
ER -