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Volume 271, Number 51, Issue of December 20, 1996 pp. 32605-32611
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Heme Binding to a Conserved Cys-Pro-Val Motif Is Crucial for the Catalytic Function of Mitochondrial Heme Lyases

(Received for publication, August 15, 1996)

Harald Steiner , Gyula Kispal , Alfred Zollner , Albert Haid , Walter Neupert and Roland Lill

From the Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie der Universität München, Goethestrasse 33, 80336 München, and the  Institut für Genetik und Mikrobiologie der Universität München, Maria-Ward-Strasse 1a, 80638 München, Federal Republic of Germany

Covalent attachment of heme to the apoforms of mitochondrial cytochromes c and c₁ requires the activity of cytochrome c heme lyase (CCHL) and cytochrome c₁ heme lyase (CC₁HL), respectively. The two enzymes differ in their cytochrome specificity, but they are related in sequence, and both contain conserved Cys-Pro-Val (CPV) motifs. By using various in vitro assays we investigated whether heme can bind directly to heme lyases and whether the CPV motif may be involved in heme binding. Heme stabilized CC₁HL, as a model protein, in a folded, protease-resistant conformation, stimulated the refolding of CC₁HL after urea denaturation, and inhibited the import of the CC₁HL precursor into mitochondria. These effects were not observed with a point mutant, CC₁HL^SPV, in which cysteine was replaced by serine, and with CC₁HL^CPV, in which the motif was deleted. These results show that heme lyases can bind heme directly, and they identify the CPV sequence as a structural element important for this interaction. The phenotype of a yeast mutant expressing CC₁HL^SPV is in good agreement with such a role of the CPV motif. The mutant cells accumulate the heme-free intermediate form of cytochrome c₁ and display a severe deficiency in the holo form. We suggest that the CPV motif forms a crucial part of the substrate binding site for heme.

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