The intrinsically disordered nature of the peroxisomal protein translocation machinery

Barros‐Barbosa, Aurora; Rodrigues, Tony A.; Ferreira, Maria João; Pedrosa, Ana G.; Teixeira, Nélson R.; Francisco, Tânia; Azevedo, Jorge E.

doi:10.1111/febs.14704

Cited by 24 publications

(24 citation statements)

References 160 publications

(305 reference statements)

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“…Interestingly, both PEX14 and PEX13 contain large intrinsically disordered regions, a property that may explain the flexibility that the DTM must possess in order to accommodate folded cargo proteins of so different sizes and shapes (reviewed in ref. [57]).…”

Section: Going Through the Peroxisomal Membrane—the Docking/translmentioning

confidence: 99%

“…The interaction between cytosolic PEX5 and the DTM is a regulated event—only cargo loaded PEX5 molecules have access to the DTM ([58] and reviewed in ref. [57])—and occurs in two sequential steps: (1) docking, a reversible interaction and (2) insertion, an essentially irreversible event in the absence of ATP [18,59]. Importantly, PEX5 at the insertion stage displays a transmembrane topology, exposing a small N-terminal domain into the cytosol whereas most of its polypeptide chain faces the organelle matrix [60].…”

Section: Going Through the Peroxisomal Membrane—the Docking/translmentioning

confidence: 99%

“…By far the strongest one involves a small globular domain in the N-terminus of PEX14, which faces the organelle matrix, and a set of eight “Short Linear Motifs” (SLiMs; [62]), the so-called pentapeptide motifs, which are present in the N-terminal half of PEX5 ([63] and reviewed in ref. [57]). Each of these PEX5 SLiMs interacts with PEX14 quite strongly (K d values from 7 to 157 nM) resulting in a high affinity/high avidity interaction between PEX5 and PEX14 at the DTM [63,64].…”

Section: Going Through the Peroxisomal Membrane—the Docking/translmentioning

confidence: 99%

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A Mechanistic Perspective on PEX1 and PEX6, Two AAA+ Proteins of the Peroxisomal Protein Import Machinery

Pedrosa

Francisco

Ferreira

et al. 2019

IJMS

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In contrast to many protein translocases that use ATP or GTP hydrolysis as the driving force to transport proteins across biological membranes, the peroxisomal matrix protein import machinery relies on a regulated self-assembly mechanism for this purpose and uses ATP hydrolysis only to reset its components. The ATP-dependent protein complex in charge of resetting this machinery—the Receptor Export Module (REM)—comprises two members of the “ATPases Associated with diverse cellular Activities” (AAA+) family, PEX1 and PEX6, and a membrane protein that anchors the ATPases to the organelle membrane. In recent years, a large amount of data on the structure/function of the REM complex has become available. Here, we discuss the main findings and their mechanistic implications.

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Section: Going Through the Peroxisomal Membrane—the Docking/translmentioning

confidence: 99%

Section: Going Through the Peroxisomal Membrane—the Docking/translmentioning

confidence: 99%

Section: Going Through the Peroxisomal Membrane—the Docking/translmentioning

confidence: 99%

See 1 more Smart Citation

A Mechanistic Perspective on PEX1 and PEX6, Two AAA+ Proteins of the Peroxisomal Protein Import Machinery

Pedrosa

Francisco

Ferreira

et al. 2019

IJMS

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“…We can speculate that functional constraints might require heterogeneous distribution of sticky residues among disordered regions. For example, the highly conserved protein PEX5 contains a long N-terminal IDR harboring several “WxxxF/Y” motifs that mediate recognition and import of proteins from the cytoplasm to the peroxisome [102]. Furthermore, random evolutionary processes are likely to result in heterogeneous stickiness patterns.…”

Section: Resultsmentioning

confidence: 99%

Protein Abundance Biases the Amino Acid Composition of Disordered Regions to Minimize Non-functional Interactions

Dubreuil

Matalon

Levy

2019

Journal of Molecular Biology

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In eukaryotes, disordered regions cover up to 50% of proteomes and mediate fundamental cellular processes. In contrast to globular domains, where about half of the amino acids are buried in the protein interior, disordered regions show higher solvent accessibility, which makes them prone to engage in non-functional interactions. Such interactions are exacerbated by the law of mass action, prompting the question of how they are minimized in abundant proteins. We find that interaction propensity or “stickiness” of disordered regions negatively correlates with their cellular abundance, both in yeast and human. Strikingly, considering yeast proteins where a large fraction of the sequence is disordered, the correlation between stickiness and abundance reaches R = − 0.55. Beyond this global amino-acid composition bias, we identify three rules by which amino-acid composition of disordered regions adjusts with high abundance. First, lysines are preferred over arginines, consistent with the latter amino acid being stickier than the former. Second, compensatory effects exist, whereby a sticky region can be tolerated if it is compensated by a distal non-sticky region. Third, such compensation requires a lower average stickiness at the same abundance when compared to a scenario where stickiness is homogeneous throughout the sequence. We validate these rules experimentally, employing them as different strategies to rescue an otherwise sticky protein fragment from aggregation. Our results highlight that non-functional interactions represent a significant constraint in cellular systems and reveal simple rules by which protein sequences adapt to that constraint. Data from this work are deposited in Figshare, at https://doi.org/10.6084/m9.figshare.8068937.v3.

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“…Peroxisome matrix protein import is driven by two conserved import receptors-Pex5 and Pex7-which recognize the proteins to be imported into peroxisomes in the cytosol (by means of their peroxisome targeting signals PTS1 and PTS2, respectively) and target them to the organelle. The import receptors converge at the docking complex, which is formed by Pex13 and Pex14 (along with Pex17 and Pex14/17 in yeasts and filamentous fungi, respectively) and that interacts with a second peroxisome membrane complex-the RING-finger complex-to compose the docking/translocation machinery (or importomer) [129]. Following docking, the import receptors are inserted into the peroxisome membrane and after releasing their cargoes they are cycled back to the cytosol.…”

Section: Sexual Development Involves a Simultaneous Regulation Of Permentioning

confidence: 99%

Dynamic Regulation of Peroxisomes and Mitochondria during Fungal Development

Navarro-Espíndola

Suaste-Olmos

Peraza-Reyes

2020

JoF

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Peroxisomes and mitochondria are organelles that perform major functions in the cell and whose activity is very closely associated. In fungi, the function of these organelles is critical for many developmental processes. Recent studies have disclosed that, additionally, fungal development comprises a dynamic regulation of the activity of these organelles, which involves a developmental regulation of organelle assembly, as well as a dynamic modulation of the abundance, distribution, and morphology of these organelles. Furthermore, for many of these processes, the dynamics of peroxisomes and mitochondria are governed by common factors. Notably, intense research has revealed that the process that drives the division of mitochondria and peroxisomes contributes to several developmental processes—including the formation of asexual spores, the differentiation of infective structures by pathogenic fungi, and sexual development—and that these processes rely on selective removal of these organelles via autophagy. Furthermore, evidence has been obtained suggesting a coordinated regulation of organelle assembly and dynamics during development and supporting the existence of regulatory systems controlling fungal development in response to mitochondrial activity. Gathered information underscores an important role for mitochondrial and peroxisome dynamics in fungal development and suggests that this process involves the concerted activity of these organelles.

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The intrinsically disordered nature of the peroxisomal protein translocation machinery

Cited by 24 publications

References 160 publications

A Mechanistic Perspective on PEX1 and PEX6, Two AAA+ Proteins of the Peroxisomal Protein Import Machinery

A Mechanistic Perspective on PEX1 and PEX6, Two AAA+ Proteins of the Peroxisomal Protein Import Machinery

Protein Abundance Biases the Amino Acid Composition of Disordered Regions to Minimize Non-functional Interactions

Dynamic Regulation of Peroxisomes and Mitochondria during Fungal Development

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