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First published online June 8, 2005
doi: 10.1242/10.1242/jcs.02364

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A phenylalanine-based folding determinant in intestinal sucrase-isomaltase that functions in the context of a quality control mechanism beyond the endoplasmic reticulum

¹ Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
² Department of Cytobiology, Philipps-University of Marburg, 35037 Marburg, Germany

^* Author for correspondence (e-mail: hassan.naim{at}tiho-hannover.de)

Accepted 9 March 2005

Phenotype II of congenital sucrase-isomaltase deficiency in man is characterized by a retention of the brush border protein sucrase-isomaltase (SI) in the ER/cis-Golgi intermediate compartment (ERGIC) and the cis-Golgi. The transport block is due to the substitution of a glutamine by a proline at amino acid residue 1098 that generates a temperature-sensitive mutant enzyme, SI_Q1098P, the transport of which is regulated by several cycles of anterograde and retrograde transport between the ER and the cis-Golgi (Propsting, M. J., Jacob, R. and Naim, H. Y. (2003). J. Biol. Chem. 278, 16310-16314). A quality control beyond the ER has been proposed that implicates a retention signal or a folding determinant elicited by the Q1098P mutation. We have used alanine-scanning mutagenesis to screen upstream and downstream regions flanking Q₁₀₉₈ and identified a putative motif, F₁₀₉₃-x-F₁₀₉₅-x-x-x-F₁₀₉₉ that is likely to be implicated in sensing the folding and subsequent trafficking of SI from the ER to the Golgi. The characteristics of this motif are three phenylalanine residues that upon substitution by alanine generate the temperature-sensitive SI_Q1098P phenotype. This mutant protein undergoes transport arrest in the ERGIC and cis-Golgi compartments and acquires correct folding and functional activity at reduced temperatures as a consequence of cycles of anterograde and retrograde transport between the ER and cis-Golgi. Other amino acid residues in this motif are not significant in the context of phenotype II. We propose that the phenylalanine cluster is required for shielding a folding determinant in the extracellular domain of SI; substitution of a Q by a P at residue 1098 of sucrase disrupts this determinant and elicits retention of SI_Q1098P in ERGIC and cis-Golgi in phenotype II of CSID.

Key words: Sucrase-isomaltase, ER-quality control, cis-Golgi, ERGIC, Protein folding, Phenylalanine-based motif

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