MEF2C
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Model warning One or more structures presented here are computational models and not experimental determinations, consequently should be treated with caution.
Description
MEF2C is member of the MEF2 family of transcription factors which bind to the mef2 DNA motif. The N-terminus is structured (MADS/MEF2 domain) and is involved in homodimerisation, DNA binding and recruitment of some protein, while the C-terminus (transcriptional activation region) is unstructured and involved in binding various other protein and includes the nuclear localisation signal.
Pictured is the MADS/MEF2 domain as a dimer (chain A and B) bound to DNA. The protein has various phosphate binding residues, and three residues that act as reader heads for specificity, namely the terminal amine of the first residue (G2), the guanidine sidechain of R3 and the terminal amine of K23. These bind to the 5'-TAT nucleobases at the centre of a mef2 motif.
The calculated Gibbs free energy of binding the DNA is small —ten-fold lower that that for the interface, as a consequence, any mutation that is close to the DNA interface is likely to have a very strong effect regardless of the interface ∆∆G.
DDD
- R3G (wild type/mutant/overlay) — ∆∆Gcomplex=0.6 kcal/mol; ∆∆GDNA interface=1.5 kcal/mol within 4Å of DNA
- K5M (wild type/mutant/overlay) — ∆∆Gcomplex=2.3 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol within 4Å of DNA
- R15P (wild type/mutant/overlay) — ∆∆Gcomplex=14.2 kcal/mol; ∆∆GDNA interface=0.3 kcal/mol within 4Å of DNA
- R15C (wild type/mutant/overlay) — ∆∆Gcomplex=3.1 kcal/mol; ∆∆GDNA interface=0.3 kcal/mol within 4Å of DNA
- K30N (wild type/mutant/overlay) — ∆∆Gcomplex=4.6 kcal/mol; ∆∆GDNA interface=1.6 kcal/mol within 4Å of DNA
- Y33D (wild type/mutant/overlay) — ∆∆Gcomplex=6.5 kcal/mol; ∆∆GDNA interface=0.2 kcal/mol
- S36R (wild type/mutant/overlay) — ∆∆Gcomplex=11.8 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R79P (wild type/mutant/overlay) — ∆∆Gcomplex=5.3 kcal/mol; ∆∆GDNA interface=0.2 kcal/mol
ClinVar
- R3S (wild type/mutant/overlay) — ∆∆Gcomplex=-0.3 kcal/mol; ∆∆GDNA interface=1.6 kcal/mol within 4Å of DNA
- R15H (wild type/mutant/overlay) — ∆∆Gcomplex=-1.3 kcal/mol; ∆∆GDNA interface=0.3 kcal/mol within 4Å of DNA
- K23R (wild type/mutant/overlay) — ∆∆Gcomplex=2.3 kcal/mol; ∆∆GDNA interface=3.1 kcal/mol within 4Å of DNA
- R24K (wild type/mutant/overlay) — ∆∆Gcomplex=2.4 kcal/mol; ∆∆GDNA interface=-0.5 kcal/mol within 4Å of DNA
- G27A (wild type/mutant/overlay) — ∆∆Gcomplex=-0.2 kcal/mol; ∆∆GDNA interface=0.6 kcal/mol within 4Å of DNA
- L38Q (wild type/mutant/overlay) — ∆∆Gcomplex=3.9 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol within 4Å of DNA
- V65G (wild type/mutant/overlay) — ∆∆Gcomplex=7.4 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
N-terminal extensions
Two mutations are not missenses, but result in a N-terminus extension. These are deleterious for DNA binding and specificity because the amino group of the flexible N-terminus hydrogen bonds to a nucleobase. The N-terminal methionine likely gets removed as it is on a flexible span of residues. The N-terminus forms a non-standard turn. Modelling an energetically favourable extension is impossible if this structure and DNA binding is kept.
Namely:
- chr5:88119613 G>A, which results in an MGT extension (wild type/mutant/overlay)
- chr5:88119631 G>A, which results in an MRERRKTGMGT extension (wild type/mutant/overlay)
gnomAD MEF2C
- V37M (wild type/mutant/overlay) — ∆∆Gcomplex=4.0 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol
- V37L (wild type/mutant/overlay) — ∆∆Gcomplex=2.8 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- S50G (wild type/mutant/overlay) — ∆∆Gcomplex=3.9 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R89K (wild type/mutant/overlay) — ∆∆Gcomplex=1.8 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
gnomAD MEF2A
- R10S (wild type/mutant/overlay) — ∆∆Gcomplex=3.1 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol
- R10C (wild type/mutant/overlay) — ∆∆Gcomplex=4.8 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- M12L (wild type/mutant/overlay) — ∆∆Gcomplex=0.2 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- L28F (wild type/mutant/overlay) — ∆∆Gcomplex=13.0 kcal/mol; ∆∆GDNA interface=-0.2 kcal/mol
- M29L (wild type/mutant/overlay) — ∆∆Gcomplex=4.7 kcal/mol; ∆∆GDNA interface=0.4 kcal/mol
- L35F (wild type/mutant/overlay) — ∆∆Gcomplex=11.2 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol
- D40E (wild type/mutant/overlay) — ∆∆Gcomplex=2.7 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- F48V (wild type/mutant/overlay) — ∆∆Gcomplex=4.9 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- S50T (wild type/mutant/overlay) — ∆∆Gcomplex=1.8 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- N52D (wild type/mutant/overlay) — ∆∆Gcomplex=0.5 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- F55V (wild type/mutant/overlay) — ∆∆Gcomplex=5.1 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol
- Q56E (wild type/mutant/overlay) — ∆∆Gcomplex=0.7 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- D61N (wild type/mutant/overlay) — ∆∆Gcomplex=1.6 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- D61H (wild type/mutant/overlay) — ∆∆Gcomplex=6.5 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- M62T (wild type/mutant/overlay) — ∆∆Gcomplex=3.6 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- D63G (wild type/mutant/overlay) — ∆∆Gcomplex=5.4 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- N73S (wild type/mutant/overlay) — ∆∆Gcomplex=1.2 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- S82L (wild type/mutant/overlay) — ∆∆Gcomplex=1.1 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- V85A (wild type/mutant/overlay) — ∆∆Gcomplex=0.2 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol
- N89K (wild type/mutant/overlay) — ∆∆Gcomplex=1.8 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
gnomAD MEF2B
- R3K (wild type/mutant/overlay) — ∆∆Gcomplex=0.2 kcal/mol; ∆∆GDNA interface=1.0 kcal/mol within 4Å of DNA
- K4Q (wild type/mutant/overlay) — ∆∆Gcomplex=1.4 kcal/mol; ∆∆GDNA interface=0.4 kcal/mol within 4Å of DNA
- Q7R (wild type/mutant/overlay) — ∆∆Gcomplex=1.2 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R10C (wild type/mutant/overlay) — ∆∆Gcomplex=4.8 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R10H (wild type/mutant/overlay) — ∆∆Gcomplex=5.9 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R10P (wild type/mutant/overlay) — ∆∆Gcomplex=1.2 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R17Q (wild type/mutant/overlay) — ∆∆Gcomplex=4.7 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol
- R17W (wild type/mutant/overlay) — ∆∆Gcomplex=7.6 kcal/mol; ∆∆GDNA interface=0.2 kcal/mol
- R24W (wild type/mutant/overlay) — ∆∆Gcomplex=2.8 kcal/mol; ∆∆GDNA interface=-0.4 kcal/mol within 4Å of DNA
- G27R (wild type/mutant/overlay) — ∆∆Gcomplex=4.1 kcal/mol; ∆∆GDNA interface=0.8 kcal/mol within 4Å of DNA
- L28V (wild type/mutant/overlay) — ∆∆Gcomplex=4.0 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol
- A32D (wild type/mutant/overlay) — ∆∆Gcomplex=10.6 kcal/mol; ∆∆GDNA interface=0.5 kcal/mol
- Y33C (wild type/mutant/overlay) — ∆∆Gcomplex=5.3 kcal/mol; ∆∆GDNA interface=0.2 kcal/mol
- E34D (wild type/mutant/overlay) — ∆∆Gcomplex=4.7 kcal/mol; ∆∆GDNA interface=1.3 kcal/mol
- V37M (wild type/mutant/overlay) — ∆∆Gcomplex=4.0 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol
- A44G (wild type/mutant/overlay) — ∆∆Gcomplex=5.3 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- I46T (wild type/mutant/overlay) — ∆∆Gcomplex=6.7 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- N49S (wild type/mutant/overlay) — ∆∆Gcomplex=4.2 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- A51T (wild type/mutant/overlay) — ∆∆Gcomplex=-0.0 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- N52S (wild type/mutant/overlay) — ∆∆Gcomplex=2.3 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- N52K (wild type/mutant/overlay) — ∆∆Gcomplex=2.1 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R53H (wild type/mutant/overlay) — ∆∆Gcomplex=3.3 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R53C (wild type/mutant/overlay) — ∆∆Gcomplex=3.9 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- T60M (wild type/mutant/overlay) — ∆∆Gcomplex=8.7 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- M62V (wild type/mutant/overlay) — ∆∆Gcomplex=7.7 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- M62I (wild type/mutant/overlay) — ∆∆Gcomplex=11.1 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R64C (wild type/mutant/overlay) — ∆∆Gcomplex=3.5 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R64H (wild type/mutant/overlay) — ∆∆Gcomplex=3.5 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- S73R (wild type/mutant/overlay) — ∆∆Gcomplex=-0.0 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- S73G (wild type/mutant/overlay) — ∆∆Gcomplex=2.8 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- E74K (wild type/mutant/overlay) — ∆∆Gcomplex=2.9 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- E77K (wild type/mutant/overlay) — ∆∆Gcomplex=7.9 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- S78N (wild type/mutant/overlay) — ∆∆Gcomplex=2.8 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R79C (wild type/mutant/overlay) — ∆∆Gcomplex=3.7 kcal/mol; ∆∆GDNA interface=0.1 kcal/mol
- R79H (wild type/mutant/overlay) — ∆∆Gcomplex=1.2 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- T82S (wild type/mutant/overlay) — ∆∆Gcomplex=0.1 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- I84M (wild type/mutant/overlay) — ∆∆Gcomplex=2.1 kcal/mol; ∆∆GDNA interface=0.3 kcal/mol
- E86K (wild type/mutant/overlay) — ∆∆Gcomplex=0.7 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- T87M (wild type/mutant/overlay) — ∆∆Gcomplex=2.0 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- L88M (wild type/mutant/overlay) — ∆∆Gcomplex=3.6 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- K89R (wild type/mutant/overlay) — ∆∆Gcomplex=0.3 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R90N (wild type/mutant/overlay) — ∆∆Gcomplex=2.2 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- R90W (wild type/mutant/overlay) — ∆∆Gcomplex=4.1 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- R91K (wild type/mutant/overlay) — ∆∆Gcomplex=0.3 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
gnomAD MEF2D
- D13N (wild type/mutant/overlay) — ∆∆Gcomplex=1.2 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- R15W (wild type/mutant/overlay) — ∆∆Gcomplex=-0.6 kcal/mol; ∆∆GDNA interface=-0.1 kcal/mol within 4Å of DNA
- R15Q (wild type/mutant/overlay) — ∆∆Gcomplex=0.9 kcal/mol; ∆∆GDNA interface=0.3 kcal/mol within 4Å of DNA
- E34Q (wild type/mutant/overlay) — ∆∆Gcomplex=3.0 kcal/mol; ∆∆GDNA interface=1.3 kcal/mol
- N49S (wild type/mutant/overlay) — ∆∆Gcomplex=4.2 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
- H50Q (wild type/mutant/overlay) — ∆∆Gcomplex=4.5 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- N52S (wild type/mutant/overlay) — ∆∆Gcomplex=2.3 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- D61N (wild type/mutant/overlay) — ∆∆Gcomplex=1.6 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- N73S (wild type/mutant/overlay) — ∆∆Gcomplex=1.2 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- K80R (wild type/mutant/overlay) — ∆∆Gcomplex=1.0 kcal/mol; ∆∆GDNA interface=0.0 kcal/mol
- A82T (wild type/mutant/overlay) — ∆∆Gcomplex=1.9 kcal/mol; ∆∆GDNA interface=-0.0 kcal/mol
Model
The model was derived as follows:
- pre-made Swissmodel homodimer based upon PDB:6BYY. (89.47% identity)
- only DNA interface crystal waters kept
- energy minimised (15 cycles) constrained to PDB:6BYY electron density map
- DNA extended due to R15
- Final 5 cycles of energy minimisation