Structure, function and biogenesis of the fungal proton pump Pma1

Area of Science:

• Biochemistry
• Molecular Biology
• Mycology

Background:

• The fungal plasma membrane proton pump Pma1 (a P-type ATPase) is crucial for maintaining cytosolic pH and plasma membrane energization.
• Pma1 is essential for fungal survival and represents a significant drug target due to its absence in animals.
• Previous characterization was limited by a lack of high-resolution structural data.

Purpose of the Study:

• To review current knowledge on the structure, function, and biogenesis of fungal Pma1.
• To highlight the impact of recent cryo-EM structural determinations on understanding Pma1.
• To discuss the implications of Pma1 structure for its stability, activity regulation, and druggability.

Main Methods:

• Review of existing literature.
• Analysis of three cryo-electron microscopy (cryo-EM) structures of fungal Pma1.
• Integration of functional, mutational, and localization studies.

Main Results:

• Three high-resolution cryo-EM structures of Pma1 in its hexameric state have been determined.
• These structures provide unprecedented insight into the molecular mechanisms governing Pma1 stability and activity.
• Structural data illuminates the protein's regulated activity and potential for drug development.

Conclusions:

• Recent structural insights into fungal Pma1 significantly advance our understanding of its molecular mechanisms.
• The unique hexameric structure of Pma1 is key to its function and stability.
• Structural information is critical for the rational design of novel antifungal therapeutics targeting Pma1.