Insertion of additional octapeptide repeats at N-terminus

N-terminal domain

The insertion modifies copper and glycosaminoglycan binding affinities [18] .

-

G114V, A117V, and G131V

Hydrophobic core

Mutations showed an effect on translocation, resulting in slightly increased generation of a topological particular transmembrane form [5] .

-

D178N

H2

Abolishment of a salt bridge between D178-R164 and possibly of hydrogen bond interactions with Y128 and Y169. Reduction of thermodynamic stability of hPrP and promotion of aggregation [14] .

It causes fatal familial insomnia in combination with M129 and familial Creutzfeldt-Jakob disease with V129.

C179A, C214A

Disulfide bridge

Mutants are insoluble and form amorphous aggregates [6] .

-

T183A

H2

Disruption of hydrogen bond interaction with Y162. Increment of the flexibility of the globular domain. Reduction of thermodynamic stability of hPrP [14] .

It causes familial Creutzfeldt-Jakob disease.

H187R

H2

Introduction of the positively charged side chain increments electrostatic repulsion between Arg156 and Arg187, which drives both side chains away from their original positions. This can lead to the solvent exposure of hydrophobic core [20] .

Related to Gerstmann-Sträussler-Scheinker syndrome

E196K

H2-H3 loop

Loss of a salt bridge between E196-R156, which destabilizes the F198 hydrophobic pocket. HA detachment of the short helix (H1) from the core, exposure of side chain F198, and formation of a nonnative strand at the N-terminus [19] .

It causes familial Creutzfeldt-Jakob disease.

F198S

Hydrophobic core

Substitution of lateral chains leaves a gap in the hydrophobic core between H2 and H3. Increment of the flexibility of the globular domain, more strongly in loop between H2 and H3 [20] .

-

V210I, Q212P

H3

The mutations increase structural disorder of the S2-H2 loop, and rise distance between S2-H2 loop and H3 which, in turn, increment the exposure of hydrophobic residues to solvent [19] [20] .

V210I causes familial Creutzfeldt-Jakob disease, and Q212P causes Gerstmann- Sträussler-Scheinker syndrome

V180I, V203I, and V210I

Hydrophobic core

Addition of an extra methylene group in lateral chains cause steric crowding. Reduction of thermodynamic stability. V180I and V210I change hydrophobic packing of H2-H3 loop residues [5] .

-

E200K

H3

The mutation modifies surface charges which influence the electrostatic interactions with other cofactors [5] .

It causes familial Creutzfeldt-Jakob disease.

Y218N

H3

Reduction of hydrophobic packing around the X-loop. Increase of the H2-H3 inter helical angle, which in turn disrupts the packing around F198 [19] . Formation of a nonnative contact between E221 and S132 on the S1-HA loop [19] .

It causes Gerstmann-Sträussler- Scheinker syndrome