Abstract
Multiple muscle-specific isoforms of the Zn2+ metalloenzyme AMP deaminase (AMPD) have been identified based on their biochemical and genetic differences. Our previous observations suggested that the metal binding protein histidine-proline-rich glycoprotein (HPRG) participates in the assembly and maintenance of skeletal muscle AMP deaminase (AMPD1) by acting as a zinc chaperone. The evidence of a role of millimolar-strength phosphate in stabilizing the AMPD-HPRG complex of both AMPD1 and cardiac AMP deaminase (AMPD3) is suggestive of a physiological mutual dependence between the two subunit components with regard to the stability of the two isoforms of striated muscle AMPD. The observed influence of the HPRG content on the catalytic behavior of the two enzymes further strengthens this hypothesis. Based on the preferential localization of HPRG at the sarcomeric I-band and on the presence of a Zn2+ binding motif in the N-terminal regions of fast TnT and of the AMPD1 catalytic subunit, we advance the hypothesis that the Zn binding properties of HPRG could promote the association of AMPD1 to the thin filament.
Highlights
AMP deaminase (AMPD) (EC 3.5.4.6) catalyzes the irreversible hydrolytic deamination of AMP to IMP and ammonia
A recent immunohistochemical study with human gastrocnemius and quadriceps femoris has shown a localization of histidine-proline-rich glycoprotein (HPRG) at the I-band level, where it shows the same distribution of actin and where AMPD1 is present in major concentration [52]
We have recently demonstrated that HPRG is preferentially localized at the I-band level, where it shows the same distribution of actin and where AMPD1 is present in major concentration [52]
Summary
AMP deaminase (AMPD) (EC 3.5.4.6) catalyzes the irreversible hydrolytic deamination of AMP to IMP and ammonia. We have summarized our previous observations that suggest that histidine-proline-rich glycoprotein (HPRG) is a subunit of AMPD1 that functions as a metallochaperone, and that a heterotetramer model for the AMPD/HPRG complex (i.e., a dimer of approximately 155 kDa heterodimers) can be envisaged [13]. On this basis, we suggest that the presence of HPRG in the striated muscle AMP deaminase complexes (AMPD1 and AMPD3) should be taken into consideration in attempts to explain the previous controversial results obtained with AMPD preparations which were partially or totally deprived of the HPRG subunits. The evidence that the formation of a protein-protein complex between HPRG and the catalytic subunit of AMPD1 is critical for the stability of the enzyme, together with the preferential localization of HPRG at the regulatory thin filament in human skeletal muscle, allows one to advance the hypothesis of a HPRG-mediated interaction between AMPD1 and fast-twitch TnT
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