LZTR1
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One protein, two phenotypes
Structure
LZTR1, Leucine-zipper-like transcriptional regulator 1, is a membrane associated protein formed of two domains.
- The C-terminus binds to Cullin3, which in turn recruits the E3 ubiquitin ligase RBX1
- The N-terminus (pictured in green) binds to hRAS (pictured in blue), resulting in its ubiquitination by RBX1.
Disease
Disease causing mutations in LZTR1 are either recessive, causing Schwannomatosis, or dominant causing Noonan syndrome. The former includes nonsense mutations (i.e. premature stops) and destabilising mutations (such as S122L), while the later group is predominantly formed by surface mutation on a specific face, which is most likely where hRAS binds.
Phosphate groups
This face has several phosphorylated residues. This is salient as phosphorylation is known to be a factor enabling hRAS binding. In fact, most of the dominant mutations are phosphorylated residues or close neighbours. In particular S244C cannot affect the binding of hRAS as serine and cysteine are the same shape, albeit with a partial charge difference; however, S244 is phosphorylated, whereas cysteine cannot be phosphorylated.
Selected mutations
Dominant:
- R97L (wild type/mutant)
- Y136C (wild type/mutant)
- S244C (wild type/mutant)
- G248R (wild type/mutant)
- M91V (wild type/mutant)
- Y119C (wild type/mutant)
- Y193N (wild type/mutant)
- S247N (wild type/mutant)
- G248R (wild type/mutant)
- R284C (wild type/mutant)
- G286R (wild type/mutant)
- H287Y (wild type/mutant)
Recessive:
- H121D (wild type/mutant)
- R170W (wild type/mutant)
- I205T (wild type/mutant)
- E217A (wild type/mutant)
- S122L (wild type/S122L)
- R170W (wild type/mutant)
- R284C (wild type/mutant)
Notes on model
The model was made by threading against PDB:5A10 using Phyre one-to-one threading (reset view). Clear defects in the model were not fixed.
Phosphorylated residues found in Phosphosite, were added using Rosetta.
The orientation of hRAS is indicative only as hRAS was docked. It was docked using the Rosetta protein-protein docking protocol with 5,000 poses and with hRAS allowed to rotate freely and translate by up to 5 Å and the lowest interface energy variant chosen after inspection of the top 10 poses.