Protein sequences encode safeguards against aggregation.
Functional requirements shaped proteins into globular structures. Under these structural constraints, which require both regular secondary structure and a hydrophobic core, protein aggregation is an unavoidable corollary to protein structure. However, as aggregation results in reduced fitness, natural selection will tend to eliminate strongly aggregating sequences. The analysis of distribution and variation of aggregation patterns in the human proteome using the TANGO algorithm confirms the findings of a previous study on several proteomes: the flanks of aggregation-prone regions are enriched with charged residues and proline, the so-called gatekeeper-residues. Moreover, in this study, we observed a widespread redundancy in gatekeeper usage. Interestingly, aggregating regions from key proteins such as p53 or huntingtin are among the most extensive "gatekept" sequences. As a consequence, mutations that remove gatekeepers could therefore result in a strong increase in disease-susceptibility. In a set of disease-associated mutations from the UniProt database, we find a strong enrichment of mutations that disrupt gatekeeper motifs. Closer inspection of a number of case studies indicates clearly that removing gatekeepers may play a determining role in widely varying disorders, such as van der Woude syndrome (VWS), X-linked Fabry disease (FD), and limb-girdle muscular dystrophy.
Reumers
Joke
J
Switch Laboratory, VIB, Vrije Universiteit Brussel, Brussels, Belgium.
Maurer-Stroh
Sebastian
S
Schymkowitz
Joost
J
Rousseau
Fréderic
F
D000465:Algorithms; D002154:Calpain / Q000737:chemistry / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000473:pathology; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D012641:Selection, Genetic
D009124:Muscle Proteins; D011506:Proteins; C105884:CAPN3 protein, human; D002154:Calpain