Mechanistic Insights into PTS2-mediated Peroxisomal Protein Import

Abstract

Prognosis in classically described dilated congestive cardiomyopathy has been reported to be related to ventricular size. Mildly dilated congestive cardiomyopathy (MDCM) has been defined as end-stage heart failure of unknown etiology (New York Heart Association class IV, left ventricular ejection fraction less than 30%), occurring with neither typical hemodynamic signs of restrictive myopathy nor significant ventricular dilatation (less than 15% above normal range). The present study includes follow-up in 12 nontransplant patients. In the first 4 months after diagnosis, two patients improved and are living, and two showed cardiac dilation and clinical deterioration and died. Six of the remaining eight with persistent MDCM died (four with intractable heart failure and two, sudden deaths) without change in ventricular size before death, despite medical therapy over 20±8 months. Eight comparable transplanted patients with persistent MDCM demonstrated improved total survival by life table analysis (p<0.05). A family history of congestive cardiomyopathy was found in nine of 16 patients (56%) with persistent MDCM. Nontransplant patients were older (p<0.02), but other findings were similar in the two groups. Endomyocardial biopsies available in 14 of 16 cases showed little or no myofibrillar loss in spite of severe hemodynamic impairment. The degree of myofibrillar loss did not correlate with hemodynamic parameters but showed good correlation with left ventricular size, that is, five of six patients with no myofibrillar loss had normal ventricular size, whereas all eight patients with mild myofibrillar loss had mild cardiomegaly (p<0.002).Our current experience suggests a somewhat variable but negative prognosis after prospective diagnosis of MDCM, with poor survival in patients with persistence of the original diagnostic features during follow-up. Preservation of heart size in MDCM is probably related to lack of significant myofibrillar loss. Thus, irrespective of heart size or myofibrillar preservation on biopsy, heart transplantation should be strongly considered in MDCM if signs of severe cardiac dysfunction persist despite therapy. (Circulation 1990;81:506-517) V entricular dilation is considered the earliest and most distinguishing morphologic feature of congestive cardiomyopathy, which is often called "dilated cardiomyopathy."1-5 Lack of significant ventricular dilation is typically found in hypertrophic and in restrictive cardiomyopathies.1,24-8 Restrictive cardiomyopathy has also been termed "nondilated cardiomyopathy" by some authors to emphasize its morphological appearance and differentiate it from dilated

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…Moreover, the basic interaction strength between a mitochondrial presequence and Tom20 (Abe et al, 2000) or between the N-terminus of a PTS2-carrying cargo protein and PEX7 is surprisingly weak (Mukai and Fujiki, 2006;Pan et al, 2013;Kunze et al, 2015), which is in good agreement with the low number of amino acids involved in this interaction. In contrast, the interaction strength between phosphorylated transit peptides and the chloroplast receptor Toc34 is drastically higher (Sveshnikova et al, 2000).…”

“…This co-receptor function for Pex7 is exerted in many organisms (metazoa and plants) by the PTS1 receptor Pex5 (Braverman et al, 1998;Otera et al, 1998;Khan and Zolman, 2010), whereas in fungi independent proteins exist for this function (Purdue et al, 1998;Titorenko et al, 1998). Cargo binding was found to be a prerequisite for the interaction of human Pex7 with its coreceptor protein Pex5 (Mukai and Fujiki, 2006;Kunze et al, 2015) and, thus, only cargo-loaded Pex7 can be transported to peroxisomes (Kunze et al, 2015). This resembles the cargo-induced translocation of Pex5 in PTS1-mediated import (Gouveia et al, 2003b).…”

“…The interaction obtains energetic contributions from several hydrophobic, but also from ionic and hydrogen bonds, which is conserved across evolution from yeast to man. However, this interaction appears to be weak until co-receptor binding transforms the cargo-bound receptor into a stable trimeric complex (Mukai and Fujiki, 2006;Pan et al, 2013;Kunze et al, 2015). This has been originally attributed to a conformational change in the receptor (Mukai and Fujiki, 2006), but the structural resolution of the yeast trimeric complex consisting of Pex7, Fox3, and a part of the yeast coreceptor Pex21 indicated that the co-receptor directly interacts with residues of the PTS2 helix ( Figure 2I) (Pan et al, 2013).…”

“…This has been originally attributed to a conformational change in the receptor (Mukai and Fujiki, 2006), but the structural resolution of the yeast trimeric complex consisting of Pex7, Fox3, and a part of the yeast coreceptor Pex21 indicated that the co-receptor directly interacts with residues of the PTS2 helix ( Figure 2I) (Pan et al, 2013). Furthermore, the interaction of Pex7 and the co-receptor is dependent on the presence of a cargo protein (Grunau et al, 2009;Kunze et al, 2015) and on the ability of Pex7 to bind the cargo protein (Kunze et al, 2015). This suggests that the co-receptor is able to discriminate PTS2-like motifs, which are bound to Pex7, but expose residues with different physical properties from the Pex7 averted side of the helix.…”

“…The primary docking of Pex5 is driven by a lipid-protein interaction (Kerssen et al, 2006), but the functional interaction is dependent on specific sequences within Pex5 that mediate the interaction with proteins of the DC (Saidowsky et al, 2001;Otera et al, 2002). In contrast, Pex7 cannot move to the peroxisomal surface by itself, but requires the interaction with a co-receptor protein, which encodes the sequence elements required for the interaction with the proteins of the docking complex (Schliebs and Kunau, 2006;Grunau et al, 2009;Kunze et al, 2015). This co-receptor function for Pex7 is exerted in many organisms (metazoa and plants) by the PTS1 receptor Pex5 (Braverman et al, 1998;Otera et al, 1998;Khan and Zolman, 2010), whereas in fungi independent proteins exist for this function (Purdue et al, 1998;Titorenko et al, 1998).…”