Peregrin: Difference between revisions
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<StructureSection load=' | <StructureSection load='2d9e' size='350' side='right' caption='Apo BRPF1 Bromodomain solved via solution NMR. (PDB entry [[2d9e]])' scene=''> | ||
== | == '''Overview''' == | ||
'''Peregrin''' (BRPF1) is a chromatin | |||
'''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. | |||
== '''PZP Domain''' == | |||
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 it associates much stronger with the nucleosome core particle than it does with the H3 tail alone<ref name="Klein_2015">PMID:26626149</ref>. | |||
== | == '''Bromodomain Structure & Acetyllysine Recognition''' == | ||
Consistent with other bromodomains, the BRPF1 bromodomain consists of a four α-helical bundle. These helices are termed <scene name='91/910741/Helical_bundle/3'>αZ, αA, αB, and αC</scene> (from N to C terminus)<ref name="Lubula_2014">PMID:25281266</ref>. There are <scene name='91/910741/Za_bc_loop/1'>two loop motifs</scene> present in its structure. The ZA loop links together the αZ and αA helices, while the BC loop links αB and αC<ref name="Lubula_2014" />. | |||
[[Image:Kac N83 PyMOL Image.JPG | thumb | 400x400px | BRPF1 Asn-83 forms a hydrogen bond with the carbonyl moiety of the acetyllysine residue. The bromodomain is shown in green. The H4K12ac peptide is shown in cyan. (PDB entry 4QYD)]] | |||
== | 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, tyrosine 40 and isoleucine 27 stabilize the acetyllysine residue through water-mediated hydrogen bonds<ref name="Lubula_2014" />. | ||
== '''PWWP Domain''' == | |||
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. Mutations of any of these aromatic residues abolishes all binding to the histone peptide<ref name="Vezzoli" />. | |||
</StructureSection> | </StructureSection> | ||
== | |||
== '''BRPF1 Association with the MOZ HAT Complex''' == | |||
The MOZ Histone Acetyltransferase Complex is a tetramer consisting of MEAF6, ING5, BRPF1 and MOZ or MORF<ref name="Klein" />. Within BRPF1, there are two non-chromatin-binding modules surrounding the PZP domain that are responsible for its association with the MOZ HAT Complex. On the N-terminal side of the PZP, lies the MOZ/MORF binding domain<ref name="Lalonde">PMID:24065767</ref>. On the other side of the PZP domain, there is a small module involved in binding to ING5 and MEAF6<ref name="Ullah">PMID:18794358</ref>. BRPF1 seems to be required for the formation of the MOZ HAT complex, as it acts as a bridge associating MOZ or MORF with ING5 and MEAF6<ref name ="Ullah" />. | |||
== '''Sequential and Structural Conservation in BRPF1''' == | |||
[[Image:Family IV bromodomain sequence alignment.JPG | thumb | 400x400px | Sequence alignment of family IV bromodomains by Clustal Omega.]] | |||
Bromodomains are categorized into several families based on sequence and structural similarity. The BRPF1 bromodomain belongs to family IV of bromodomains<ref name="Lloyd">PMID:28500727</ref>. Out of these bromodomain proteins, the BRPF3 bromodomain has the highest sequence identity with that of BRPF1 (66.2%). A specific asparagine residue is conserved across all bromodomains due to its integral role in acetyllysine recognition. | |||
PWWP domains have very low sequence and structural conservation. In fact, BRPF1 actually contains a PSYP motif rather than the canonical PWWP motif, however this change doesn't impact its ability to recognize methylated lysine. Furthermore, while many PWWP domains contain a β-barrel, there are significant differences in other structural aspects among PWWP domains<ref name="Hong">PMID:21720545</ref>. The aromatic cage in the β-barrel is a conserved structure and is necessary for methyllysine binding<ref name="Hong" />. | |||
== '''Links to Human Disease''' == | |||
BRPF1 has been implicated in the progression of several cancers. Chromosomal translocations of the gene encoding MOZ (a subunit in the MOZ HAT complex) have been linked to the development of acute myeloid leukemia <ref name="Obi" />. The crucial role of BRPF1 in this complex has made it the subject of many studies in order to understand how this mutation leads to cancer. Another study reported an association between upregulation of the BRPF1 gene and poor survival rates in hepatocellular carcinoma patients <ref>PMID:34285329</ref>. | |||
Mutations within the gene itself have been associated with neurological disorders and widespread reduced histone acetylation <ref name="Yan" />. | |||
==Peregrin PDB structures== | |||
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}} | ||
{{#tree:id=OrganizedByTopic|openlevels=0| | {{#tree:id=OrganizedByTopic|openlevels=0| | ||
* Peregrin | * Peregrin; Domains – PZP 274-450; bromodomain 626-740; PWWP 1079-1207 | ||
**[[3l42]] – hBRPF1 PWWP domain - human<br /> | **[[3l42]] – hBRPF1 PWWP domain - human<br /> | ||
**[[5erc]] – hBRPF1 PZP domain<br /> | **[[5erc]] – hBRPF1 PZP domain<br /> | ||
**[[ | **[[4lc2]], [[7c4i]] – hBRPF1 bromodomain <br /> | ||
**[[ | **[[2d9e]] – hBRPF1 bromodomain - NMR<br /> | ||
* Peregrin complexes | * Peregrin complexes | ||
**[[5ewv]], [[5eww]], [[5c89]], [[5g4r]], [[5g4s]], [[5em3]], [[5ev9]], [[5eva]], [[5ewh]], [[5c85]], [[5c87]], [[5d7x]], [[5dy7]], [[5d7a]], [[5dyc]], [[5e3d]], [[5e3g]], [[5epr]], [[5eps]], [[5eq1]], [[5etb]], [[5etd]], [[5ewc]], [[5ewd]], [[5ffy]], [[5c7n]], [[4uye]] – hBRPF1 bromodomain + ligand <br /> | **[[5ewv]], [[5eww]], [[5c89]], [[5g4r]], [[5g4s]], [[5em3]], [[5ev9]], [[5eva]], [[5ewh]], [[5c85]], [[5c87]], [[5d7x]], [[5dy7]], [[5d7a]], [[5dyc]], [[5e3d]], [[5e3g]], [[5epr]], [[5eps]], [[5eq1]], [[5etb]], [[5etd]], [[5ewc]], [[5ewd]], [[5ffy]], [[5c7n]], [[4uye]], [[5dya]] – hBRPF1 bromodomain + ligand <br /> | ||
**[[5ffv]], [[5ffw]], [[4qyd]], [[4qyl]] – hBRPF1 bromodomain + histone peptide<br /> | **[[5ffv]], [[5ffw]], [[4qyd]], [[4qyl]] – hBRPF1 bromodomain + histone peptide<br /> | ||
**[[2rs9]] – hBRPF1 bromodomain + histone peptide - NMR<br /> | **[[2rs9]] – hBRPF1 bromodomain + histone peptide - NMR<br /> | ||
**[[3mo8]], [[2x4w]], [[2x4x]], [[2x4y]], [[2x35]] – hBRPF1 PWWP domain + histone peptide<br /> | **[[3mo8]], [[2x4w]], [[2x4x]], [[2x4y]], [[2x35]] – hBRPF1 PWWP domain + histone peptide<br /> | ||
**[[5fg5]], [[5fg4]] – hBRPF1 bromodomain + chemical probe<br /> | **[[5fg5]], [[5fg4]], [[5myg]] – hBRPF1 bromodomain + chemical probe<br /> | ||
**[[5t4u]], [[5t4v]], [[5mwg]], [[5mwh]], [[5mwz]], [[5o4s]], [[5o4t]], [[5o55]], [[5o5a]], [[5o5f]], [[5o5h]], [[5ov8]], [[5owa]], [[5owb]], [[5owe]], [[6ekq]] – hBRPF1 bromodomain + inhibitor<br /> | |||
**[[5c6s]] – hBRPF1 PWWP domain + ligand <br /> | **[[5c6s]] – hBRPF1 PWWP domain + ligand <br /> | ||
}} | }} | ||
== References == | |||
== '''References''' == | |||
<references/> | <references/> | ||
[[Category:Topic Page]] | |||