Peregrin: Difference between revisions

'''Peregrin''', also known as Bromodomain and PHD Finger-containing 1 ('''BRPF1''') is a 137 kDa protein that plays a versatile role in epigenetic signaling events. It contains three chromatin reader domains, including a <scene name='91/910741/Apo_bromodomain/1'>bromodomain</scene>, <scene name='91/910741/Apo_pzp/1'>PZP domain</scene> (two PHD fingers separated by a Zinc Knuckle), and '''proline-tryptophan-tryptophan-proline (<scene name='91/910741/Pwwp_unliganded/1'>PWWP</scene>) domain''' (from N to C terminus)<ref name="Yan">PMID:27939640</ref>. Through these three domains, it is capable of recognizing both modified and unmodified histones, as well as non-specifically binding DNA <ref name="Klein">PMID:31711755</ref>,<ref name="Glass1">PMID:24333487</ref>. BRPF1 carries out its function as a component of the MOZ (monocytic leukemic zinc-finger protein) histone acetyltransferase (HAT) complex <ref name="Obi">PMID:33554132</ref>. This complex is involved in the regulation of gene expression, particularly those involved with skeletal development, hematopoiesis, and neurodevelopmental processes <ref>PMID:19254709</ref>,<ref>PMID:27500495</ref>,<ref name="Klein" />. Accordingly, it has the greatest tissue distribution in the bone marrow and brain.

The PZP domain of BRPF1 is located at its N-terminus and has been shown to <scene name='91/910741/Pzp_with_h3/2'>associate with the histone H3 tail</scene> <ref name="Klein" />. Three residues in the H3 peptide undergo unique interactions with the binding pocket. These are <scene name='91/910741/H3_ala_1/1'>Ala-1</scene>, <scene name='91/910741/Arg_2/1'>Arg-2</scene>, and <scene name='91/910741/Thr-3/1'>Thr-3</scene>.<ref name="Klein" />. In addition to its binding to the histone H3 N-terminus, the PZP domain can associate non-specifically with DNA. It is thought that this interaction is mediated by lys-383, lys-390, and arg-392<ref name="Klein" />. These residues form a <scene name='91/910741/Positive_patch_pzp/1'>positively charged patch</scene> in the second PHD finger that can interact with the negative DNA backbone. Interestingly, the DNA- and histone H3-binding capabilities of the PZP domain seem to work in tandem, as is associates much stronger with the nucleosome core particle than it does with the H3 tail alone<ref name="Klein_2015">PMID:26626149</ref>.

The BRPF1 bromodomain has been shown to recognize and bind to various acetylated lysine marks on the N-terminal tails of histones tails <ref name="Glass1" />. It preferentially binds to histone H4 acetylated at positions K5 ([[2rs9]]), K8, and K12 ([[4qyd]]) as well as H3 and H2A (([[4qyl]]) at position K14 and K5, respectively<ref name="Obi" />,<ref name="Glass1" />. Interestingly, the BRPF1 bromodomain has also been shown to bind di-acetylated histone peptides as a monomer with high affinity, including H4K5acK8ac and H4K5acK12ac <ref name="Obi" />. Acetyllysine recognition is coordinated by a number of residues in the bromodomain's binding pocket. Using NMR chemical shift perturbation experiments, Glass et al. reported several <scene name='91/910741/Nmr_resi_h4_binding/1'>key residues</scene> the undergo conformational changes upon histone H4 ligand binding (I27, L34, E36, V37, N83, and I88)<ref name="Obi" />. Notably, asparagine 83 was among these. The interaction between the amide nitrogen of asparagine with the carbonyl of the acetyllysine group is conserved in all bromodomains and is necessary for binding to occur <ref name ="Obi" />,<ref name ="Lubula_2014" />. Furthermore, the tyrosine 40 and isoleucine 27 stabilize the acetyllysine residue through water-mediated hydrogen bonds<ref name="Lubula_2014" />.   

PWWP domains are a weakly conserved protein module that often contain a proline-tryptophan-tryptophan-proline motif and have been show to recognize methylated histones<ref name="chen">PMID:11836534</ref>. The BRPF1 PWWP domain has high selectivity for histone H3 Lys-36 ([[2x4w]]) that has been trimethylated (H3K36me3)<ref name="Vezzoli">PMID:20400950</ref>. The trimethyl mark at H3K36 has gained a lot attention due to its established roles is RNA splicing and developmental disorders<ref name="Paulina">PMID:19182803</ref>,<ref name="Nimura">PMID:19483677</ref>. Recognition of H3K36me3 is strongly dependent on the <scene name='91/910741/Pwwp_aromatic_cage/1'>aromatic cage</scene>, which consists of Tyr-1096, Tyr-1099, and Phe-1147.

== '''Available Structures''' ==

Bromodomain (apo): [[2d92]]

Bromodomain w/ histone peptides: [[4qyl]], [[4qyd]], [[5ffv]], [[5ffw]]

Bromodomain w/ inhibitors: [[6ekq]], [[5ov8]], [[5o5h]], [[5o5f]], [[5o5a]], [[5o55]]

PZP (apo): [[5erc]]

PZP w/ histone H3 peptide: [[6u04]]

PWWP (apo): [[2x35]]

PWWP w/ H3K36me3: [[2x4w]], [[2x4y]], [[2x4x]]