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Structural evidence of functional divergence in human alkaline phosphatases
Marie-Hélène Le Du1, Jose Luis Millan
1Département d'Ingénierie et d'Etudes des Protéines (DIEP), CEA, Bat 152 C. E. Saclay, 91191 Gif-sur-Yvette Cedex, France. mhledu@cea.fr
The Journal of Biological Chemistry
|October 10, 2002
Summary
Structural analysis reveals alkaline phosphatase (AP) isozymes exhibit distinct dimerization capabilities and active site features. These differences suggest specialized substrate specificities among intestinal, germ cell, placental, and tissue-nonspecific AP forms.
Area of Science:
- Biochemistry
- Structural Biology
- Genetics
Background:
- The alkaline phosphatase (AP) gene family comprises multiple human isozymes.
- These include tissue-nonspecific AP (TNAP) and tissue-specific forms: intestinal (IAP), germ cell (GCAP), and placental (PLAP).
Purpose of the Study:
- To elucidate structural distinctions between human AP isozymes.
- To understand the implications of these structural differences on protein function and substrate specificity.
Main Methods:
- Comparative structural analysis of AP isozymes.
- Molecular modeling of TNAP, IAP, and GCAP based on the PLAP structure.
- Examination of monomer-monomer interfaces and active site cleft regions.
Main Results:
- The monomer-monomer interface analysis revealed that IAP, GCAP, and PLAP can form heterodimers, but TNAP cannot form heterodimers with these tissue-specific isozymes.
- Mapping of the active site cleft identified distinct structural features for each AP isozyme.
- A unique structural fingerprint was determined for the active site of each AP isozyme.
Conclusions:
- Structural variations in the monomer-monomer interface and active site cleft contribute to the functional divergence of AP isozymes.
- These findings suggest that different AP isozymes have evolved distinct substrate specificities.