Research Highlights


neurology cover
The work was featured on the cover of Neurology


DNM1 encephalopathy: A new disease of vesicle fission.

  • The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies.
  • Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date.
  • Given the predicted dominant-negative mechanism of this mutation, patients with this variant presents a prime target for therapeutic discovery and intervention.

Neurology. 2017 Jul 25;89(4):385-394.

huether nature communication


The landscape of somatic mutations in epigenetic regulators across 1000 pediatric cancer genomes.

  • To define the landscape of somatic mutations in epigenetic regulators in pediatric cancer, we identified 633 genes that bind, modify or establish complexes on a histone peptide, reorganize nucleosomes, or modify or bind modified genomic DNA. 
  • The exons from the 633 genes were sequenced in 21 pediatric cancers from 1023 paired tumors.
  • Novel SNVs in the deubiquitinase USP7 were uncovered in T-cell acute lymphoblastic leukemia.  Cellular assays on two mutations, C300R and D305G, correlated with a decrease in the deubiquitination of its target H2B ubiquityl Lys120.  These loss-of-function mutations occur at the binding interface between the USP7 and ubiquitin.

Nat Commun. 2014 Apr 8;5:3630


Sequence Fingerprint and Structural Analysis of the A3DFK9 SCOR Enzyme from Clostridium thermocellum. 

  • The SCOR protein from industrial important  bacterium C. thermocellum contains a Cys84 in a highly conserved Gly84 and a Gly106 in a highly conserved Asn106 position. 
  • The structure revealed the N-G and G-C double variation is critical because the mutation of G84 to C84 would clash with the A103.  The presence of any other residue  besides Gly in the Asn position would sterically be prohibited (PDB:3GED [Green] and PDB:1HDC [Teal]). Further, the C84 could not coordinating the water wire and proton release to bulk solvent. However, there is a direct line of water molecules <3.5A from the catalytic Lys through the protein. 
  • Interestingly, as a breaker in the helix, Pro110 influences G106 carbonyl, making it available to hydrogen bond explaining the amino acid switch and retention of the “water wire” important for connecting the catalytic site to bulk solvent. 

Proteins. 2010 Feb 15;78(3):603-13.

q9hya2 atypical catalytic center
The short chain oxidoreductase Q9HYA2 from Pseudomonas aeruginosa PAO1 contains an atypical catalytic center.

  • We identified a SCOR protein with an atypical catalytic center of Arg-Ser-Thr in the bacterium Pseudomonas aeruginosa.  This atypical catalytic center and their operons were identified in 86 additional bacterial species (left image) .
  • Structural alignment to a a typical SCOR, polyketide ketoreductase (KR), demonstrated that Q9HYA2’s Ser146 and Arg163 superimposed upon the KR’s catalytic  Ser144 and Lys161, respectively (right image).
  • A chloride ion is bound at the position normally occupied by the catalytic tyrosine hydroxyl.  The putative active site of Q9HYA2 contains a chemical moiety at each catalytically important position of a typical SCOR enzyme.

Robert Huether