MnM - Minimotif Miner

Sample Analysis of Prion Protein (NP_000302)

We have analyzed Prion protein (NP_000302). Prion is an interesting example because a D178N mutation causes disease {}. Allelic variation of the 128 position determines whether individuals get Creutzfeldt-Jakob disease (V128) or fatal familial insomnia (M128)(Goldfarb,.Science. 1992). Analysis of Prion with MnM predicts 39 potential functional motifs in Prion protein. Six such motifs were already experimentally confirmed and five motifs were closely related to known effects of Prion and are consistent with published experiments. Painting potential functions onto the surface of Prion protein (Fig. 1) provides an example of how MnM can be used for predicting new functions in proteins and generating new hypotheses for how mutations cause disease. In this case, the 128V variant that favors Creutzfeldt-Jakob disease eliminates a potential Vav2 SH2 binding motif (yellow) that is present in the 128M variant that favors Fatal familial insomnia. Also, the D178N disease associated mutation eliminates a potential Caspase 1 cleavage site (cyan). The Caspase apoptotic cascade is activated by Prion. Several other motifs (N-glycosylation, Grb2-SH2 binding, predicted by MnM surround these important mutations and may be responsive to mutation and/or allelic variation. Several motifs predicted on the opposing face of the protein or on fragments of Prion not shown in this structure are not shown.