Molecular basis of substrate recognition and degradation by human presequence protease

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Human presequence protease (hPreP) is a mitochondrial metalloprotease crucial for maintaining proteostasis.
• hPreP degrades toxic peptides, including mitochondrial presequences and amyloid-beta (Aβ), implicated in Alzheimer disease.

Purpose of the Study:

• To elucidate the structural basis of hPreP's substrate recognition and degradation mechanisms.
• To investigate the role of hPreP in the context of Alzheimer disease pathogenesis.

Main Methods:

• X-ray crystallography was used to determine the structures of hPreP alone and in complex with Aβ.
• Small-angle X-ray scattering (SAXS) was employed to analyze hPreP's conformational dynamics in solution.

Main Results:

• Crystal structures reveal hPreP utilizes size exclusion and charge complementation for substrate binding.
• hPreP possesses unique features enabling the capture, cleavage, and destruction of amyloidogenic properties in diverse peptides.
• SAXS analysis indicates hPreP exists in a dynamic equilibrium between closed and open states, preferring the closed conformation.
• Aβ binding induces a closed hPreP state and promotes dimerization.

Conclusions:

• The study reveals the molecular mechanisms underlying hPreP's flexible yet specific substrate recognition and degradation.
• Understanding hPreP's function provides insights into mitochondrial proteostasis and potential therapeutic strategies for Alzheimer disease.