Abstract
Metallochaperones function as intracellular shuttles for metal ions. At present, no evidence for the existence of any eukaryotic zinc-chaperone has been provided although metallochaperones could be critical for the physiological functions of Zn2+ metalloenzymes. We propose that the complex formed in skeletal muscle by the Zn2+ metalloenzyme AMP deaminase (AMPD) and the metal binding protein histidine-proline-rich glycoprotein (HPRG) acts in this manner. HPRG is a major plasma protein. Recent investigations have reported that skeletal muscle cells do not synthesize HPRG but instead actively internalize plasma HPRG. X-ray absorption spectroscopy (XAS) performed on fresh preparations of rabbit skeletal muscle AMPD provided evidence for a dinuclear zinc site in the enzyme compatible with a (μ-aqua)(μ-carboxylato)dizinc(II) core with two histidine residues at each metal site. XAS on HPRG isolated from the AMPD complex showed that zinc is bound to the protein in a dinuclear cluster where each Zn2+ ion is coordinated by three histidine and one heavier ligand, likely sulfur from cysteine. We describe the existence in mammalian HPRG of a specific zinc binding site distinct from the His-Pro-rich region. The participation of HPRG in the assembly and maintenance of skeletal muscle AMPD by acting as a zinc chaperone is also demonstrated.
Highlights
Transition metal ions play an essential role in many major processes in biochemistry
The ligand displacement that presumably occurs when substrate enters the zinc coordination sphere of AMP deaminase (AMPD) is consistent with a cocatalytic mechanism [52]
A model has been proposed for the dinuclear Zn site in rabbit skeletal muscle AMPD (Figure 1A)
Summary
Transition metal ions play an essential role in many major processes in biochemistry. The possibility that the primary structure of rabbit plasma HPRG reported by Borza et al [62] was wrongly determined is further strengthened by the presence in the sequence reported by Borza et al [62] of one methionine residue (Met-424); in contrast, no methionine residues are present in the HPRG sequence that has been derived from the rabbit genome sequence It has recently been observed [71] that none of the three constituent peptides of the incubation mixture at the end of the CNBr treatment of HPRG dissociated from rabbit skeletal muscle AMP deaminase showed the amino-terminal sequence corresponding to the sequence. The above observations are in agreement with the results of a recent investigation on the origin of skeletal muscle HPRG that have reported that skeletal muscle cells do not synthesize the protein but can instead actively internalize plasma HPRG [74] and strongly suggest that the HPRG found in skeletal muscle is identifiable with the protein that must be acquired from plasma
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