Question: No Prominent Change in Structure of Mutated Proteins
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gravatar for ammarsabir15
2.2 years ago by
ammarsabir1560
ammarsabir1560 wrote:

I am working on Parkinson disease causing protein PINK1, I am focusing on 26 disease causing variants for parkinson. These variants are reported here.

There is no PDB structure for PINK1, thus I predicted it using I-Tasser. I used this structure for homology modelling through modeller. By inducing the mutation at the specific site for each variant in the sequence of PINK1, I predicted 26 structures for all the variants. The protein sequence was obtained from ensemble.

But there is no significant change in the structure of PINK1 for wild type and mutated proteins. (RMSD values below 0.4 were considered insignificant).

If there is not significant change in structure then what could be the possible mechanism through which these variants are contributing to Parkinson disease?

ADD COMMENTlink modified 2.2 years ago by Joe18k • written 2.2 years ago by ammarsabir1560
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gravatar for WouterDeCoster
2.2 years ago by
Belgium
WouterDeCoster45k wrote:

An obvious solution would be that your structure prediction is not accurate. But in addition to that, there are other mechanisms through which a mutation can cause a pathogenic effect. For example, the substitution could lead to a loss of enzymatic function, or change the affinity for binding to an interacting protein.

ADD COMMENTlink written 2.2 years ago by WouterDeCoster45k
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gravatar for Joe
2.2 years ago by
Joe18k
United Kingdom
Joe18k wrote:

I don’t see much of a reason to start with ITasser then use modeller. Instead just feed ITasser with the sequences of all the mutated proteins and simulate each structure de novo. ITasser should generate pretty equivalent structures anyway.

By using modeller, you’re starting from a model that might be wrong and just amplifying the problems. Modeller will attempt to minimise the differences as it is threading based. So is ITasser, but it has more ab initio steps. Threading can have the effect of ‘over fitting’ your mutated sequences, which then suppresses the differences. Some molecular dynamics steps to allow the structures to relax might be useful too (I’m not sure if modeller includes an energy minimisation step, though I know ITasser does).

If the models are accurate (unlikely), its possible that structural variation isn’t the whole answer. The structure might be very similar, but an amino acid change alters Ionic strength (and therefore pI), rigidity, ligand binding etc.

ADD COMMENTlink written 2.2 years ago by Joe18k
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