Structural Fuzziness of the RNA-Organizing Protein SERF Determines a Toxic Gain-of-interaction

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Protein complex conversion from functional to pathogenic states is under intense research.
• Protein conformational disorder, termed structural fuzziness, can induce unfavorable interactions.

Purpose of the Study:

• To investigate how structural fuzziness in protein complexes influences their functional and pathogenic roles.
• To elucidate the mechanism by which SERF1a transitions from an RNA-binding factor to a pathogenic enhancer of alpha-synuclein (aSyn) amyloid toxicity.

Main Methods:

• Studied the intrinsically disordered protein SERF1a and its interaction with RNA and alpha-synuclein (aSyn).
• Analyzed the role of conformational disorder in the bound state of SERF1a.
• Investigated binding affinities and modes of interaction between SERF1a, RNA, and aSyn.

Main Results:

• Extreme conformational disorder in bound SERF1a transforms it into a pathogenic enhancer of aSyn amyloid toxicity.
• SERF1a promotes RNA incorporation into nucleoli and RNA-organelles due to its disordered state.
• SERF1a exhibits undifferentiated binding to both RNA and aSyn at an identical charged site, with similar affinities and no disorder-to-order transition.
• Under cellular stress, the pro-amyloid aSyn:SERF1a interaction prevails over non-toxic RNA binding.

Conclusions:

• Structural fuzziness in SERF1a leads to an adverse gain-of-interaction, favoring toxic aSyn binding.
• This mechanism links protein conformational flexibility, amyloid aggregation, and RNA process malfunction, characteristic of neurodegenerative proteinopathies.
• Fuzzy disorder in protein complexes provides a direct link to pathogenic processes in neurodegenerative diseases.