Structural basis for the functional differences between type I and type II human methionine aminopeptidases

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Methionine aminopeptidases (MetAPs) are crucial enzymes involved in protein maturation.
• Human cells express two types of MetAP: Type I (MetAP1) and Type II (MetAP2).
• MetAP2 is a validated target for anti-angiogenesis therapies, while MetAP1's role is less understood.

Purpose of the Study:

• To determine the crystal structure of human MetAP1.
• To compare the structural features of MetAP1 with MetAP2.
• To elucidate the molecular basis for differential inhibitor and substrate specificity.

Main Methods:

• X-ray crystallography was used to determine the three-dimensional structure of human MetAP1.
• Structural comparisons were performed between MetAP1 and previously reported MetAP2 structures.
• Biochemical assays were conducted to investigate the effect of metal ions and substrate interactions.

Main Results:

• The crystal structure of human MetAP1 was determined, revealing an active site distinct in size and shape from MetAP2.
• The active site of MetAP1 is too small to accommodate inhibitors like ovalicin, explaining their selective targeting of MetAP2.
• Excess cobalt ions were observed to bind to the MetAP1 active site, explaining metal-ion-induced inhibition.
• The N-terminal region of MetAP1 contains Pro-x-x-Pro motifs, suggesting a potential role in ribosome binding.

Conclusions:

• Structural differences between MetAP1 and MetAP2 explain their distinct inhibitor specificities and substrate preferences.
• The findings provide insights into the regulation of MetAP activity by metal ions.
• The N-terminal motifs of MetAP1 suggest a functional link to protein synthesis machinery.