 The cellular prion protein, PRPC, consists of a natively unstructured N-terminal domain, which includes an optorepeat region, OR, and a linker, followed by a C-terminal domain that misforms into PRPSC in Kreutzfeldt-Jakob disease. PRPC beta endoproteolysis to the C2 fragment allows for PRPSC formation, while alpha endoproteolysis prevents its formation. To examine the OR, researchers design new alleles, S1 and S3, which were locked in extended or compact conformations, respectively. These alterations resulted in PRP that resembles wild-type PRP in supporting peripheral nerve myelination. However, prion-infected S1 and S3 transgenic mice both accumulate low levels of PRPSC and infectious prions, but with different clinical presentations. Surprisingly, S3-PRP overproduces C2 fragments in the brain through a mechanism distinct from metal-catalyzed hydrolysis reported previously. It was concluded that OR flexibility influences various biological outcomes, and can either decouple or engage. This article was authored by Agnes Lau, Alex McDonald, Natalie Dawd, and others. We are article.tv, links in the description below.