Protein arginine N-methyltransferase 7

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Description

Protein arginine N-methyltransferase 7, encoded by PRMT7, is a SAM dependent methyltransferase that acts on specific arginines in two small nuclear ribonucleoproteins and histone H4. These substrates are highly positively charged, while the PRMT7 features a cavity with a strong negative charge next to the SAM cofactor, suggesting this may be the binding region with the substrates.

Structurally, it can form a homodimer, but the monomer itself is a pseudodimer. Composed of:

N-terminal SAM binding domain
N-terminal beta barrel
N-terminal dimerisation arm
C-terminal SAM binding domain
C-terminal dimerisation arm
C-terminal beta barrel

A variety of variants have been described:

Family 1

Reported in Valenzuela et al. 2018

Compound het:

p.Glu144fs (remnant/missing/overlay)
p.Val416fs (remnant/missing/overlay)

Family 2

Reported in Kernohan et al. 2017

Homozygous large scale genomic deletion

Family 3

Reported in Akawi et al. 2015

Compound het:

Altered splicing
p.Trp494Arg (wild type/mutant/overlay). A buried pi-stacking tryptophan is replaced by a differently shaped charged residues resulting in a large loss of stability (∆∆G=11 kcal/mol)

Family 4

Reported in Akawi et al. 2015

Compound het:

p.Arg32Thr (wild type/mutant/overlay). This mutation has a near neglible effect on protein folding (+1.8 kcal/mol), however thsi residue is frequently found monomethylated (cf. PhosphositePlus)
p.Arg387Gly (wild type/mutant/overlay). This mutation replaces an arginine, which forms two salt bridges, with glycine, the smallest residue, resulting in ∆∆G of 5 kcal/mol.

Family 5

Reported in Akawi et al. 2015 and our study

Compound het:

Altered splicing
p.Arg32Thr (wild type/mutant/overlay)). Discussed above.

Family 6

Reported in Birnbaum et al. 2018

Homozygous:

p.Arg358fs*9 (remnant/missing/overlay)

Family 7

Reported in Agolini et al. 2018 and our study

Homozygous:

p.Glu108Ter (remnant/missing/overlay)

Family 8

Reported in Agolini et al. 2019

Homozygous:

p.Arg497Gln (wild type/mutant/overlay). This mutation to a shorter residue results in a less satified charge interaction, resulting in a ∆∆G of 8 kcal/mol.

Family 9

Reported in Dr. Ghada

Homozygous:

p.Gln64* (remnant/missing/overlay)

Family 10

Reported in Mario Bengala

Compound het:

p.Met81del (wild type Met81/wild type helix+loop/variant helix+loop/overlay (backbone)/overlay (residues)). This deletion removes a residue from an α helix close to the SAM ligand. As a result there are three possibilities, (a) a hairpin is formed, which is not structurally possible (∆∆G over 50 kcal/mol), (b)/(c) residues on one of the sides would be shifted by 100°, as one side is part of the substrate binding pocket, this would result in a loss of function, however the far side of the helix cannot satisfactorily accomdate the change (∆∆G 27 kcal/mol). Therefore this variant is deleterious under all three options.
Altered splicing

Family 11

Reported in LOVD

Compound het:

p.Leu78Phefs*24 (remnant/missing/overlay)
Genomic rearrangement

Family 12

Reported in our study

Homozygous:

p.Tyr670Metfs*27 (remnant/missing/overlay)

Family 13

Reported in our study

Homozygous:

p.Glu94Lys (wild type/mutant/overlay)). This is a destabilising mutation (15 kcal/mol without bound SAH), majorly it replaces a SAM-binding negatively charged residue for a positive one as a result SAM binding is highly abrogated (-28 kcal/mol to -15 kcal/mol).

Family 14

Reported in our study

Compound het:

Altered splicing
p.Glu125Gly (wild type/mutant/overlay). This mutation replaces a surface glutamate with a glycine. However, the residue is part of turn and hydrogen bonds with His122 backbone, consequently the loss of hydrogen bonding results in a ∆∆G of +8 kcal/mol. Furthermore, it is less than 8 Å away from SAM.

Family 15

Reported in our study

Compound het:

p.Cys226Thrfs*4 (remnant/missing/overlay)
p.Tyr334Leufs*8 (remnant/missing/overlay)

Family 16

Reported in our study

Compound het:

Altered splicing
p.Arg274* (remnant/missing/overlay)

Family 17

Reported in our study

Compound het:

Altered splicing
p.Cys571Arg (wild type/mutant/overlay). Cys571 and Cys639 do not form a disulfide bond in the mouse PDB:4C4A, which was expressed in a baculovirus expression system, even if their Cβ are 5 Å apart.

Family 18

Reported in our study

Compound het:

p.I292Sfs*45 (remnant/missing/overlay)
p.Glu160Profs*5 (remnant/missing/overlay)

Family 19

Reported in our study

Homozygous:

p.Q369X (remnant/missing/overlay)

Family 20

Reported in our study

Compound het:

p.Cys671* (remnant/missing/overlay)
Altered splicing

Family 21

Reported in our study

Homozygous:

p.Gln28Ter (remnant/missing/overlay)

Family 22

Reported in DECIPHER 317828

Homozygous:

p.Leu78PhefsTer24 (remnant/missing/overlay)

Family 23

Reported in DECIPHER 305814

Compound het:

p.Lys115IlefsTer13 (remnant/missing/overlay)
p.Arg32Thr (wild type/mutant/overlay)

Family 24

Reported in our study

Homozygous:

Altered splicing

Methods

Methods and models are deposited in github.

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