A twist in the ABC: regulation of ABC transporter trafficking and transport by FK506‐binding proteins

Abstract

Post‐transcriptional regulation of ATP‐binding cassette (ABC) proteins has been so far shown to encompass protein phosphorylation, maturation, and ubiquitination. Yet, recent accumulating evidence implicates FK506‐binding proteins (FKBPs), a type of peptidylprolyl cis–trans isomerase (PPIase) proteins, in ABC transporter regulation. In this perspective article, we summarize current knowledge on ABC transporter regulation by FKBPs, which seems to be conserved over kingdoms and ABC subfamilies. We uncover striking functional similarities but also differences between regulatory FKBP‐ABC modules in plants and mammals. We dissect a PPIase‐ and HSP90‐dependent and independent impact of FKBPs on ABC biogenesis and transport activity. We propose and discuss a putative new mode of transient ABC transporter regulation by cis–trans isomerization of X‐prolyl bonds.

A phospho-switch provided by LRR receptor-like kinase, ALK1/QSK1/KIN7, prioritizes ABCG36/PEN3/PDR8 transport toward defense

“…4A), can have such a drastic effect on ABCG36 substrate specificity. One explanation might be that these regions function in analogy to the regulatory linker or R-domains connecting the two halves of full-size transporters of ABCBs or CFTR/ABCC7, respectively, and where phosphorylation is thought to add negative charges that by means of conformational changes altering ABC functional capacities (Aryal et al, 2015; Gadsby et al, 2006; Geisler and Hegedus, 2020). This model was very recently supported by cryo-EM imaging of the ABCC, yeast cadmium factor (YCF1), showing that the YCF1 R-domain associates upon phosphorylation with NBD1 altering directly its ATPase activity (Khandelwal et al, 2022).…”

A Retro-Perspective on Auxin Transport

“…Furthermore, a gene duplication event in the ABC transporter family (Ogasawara et al, 2020) hindered their identification in classical genetic screens (Zhang et al, 2018). In between, based on the identification of a signature D/E-P motif for auxin transporting ABCBs (ATAs) it was suggested that 11 of the 22 full-size ABCBs are ATAs (Geisler and Hegedus, 2020;Hao et al, 2020). In between, functional redundancy between similar ATA isoforms could be solved by using clade-specific gene silencing (Zhang et al, 2018).…”

“…As a result, abcb1 abcb19 plants resemble the twd1 mutant and show similar PAT defects (Geisler et al, 2003; see Figure 1). However, auxin-transporting ABCBs (ATAs) contain an essential proline as part of a diagnostic D/E-P motif in their C-terminal nucleotidebinding folds that is essential for auxin transport but not for trafficking (Geisler and Hegedus, 2020;Hao et al, 2020). Thus, TWD1 might have a dual role in ABCB activation and secretion, respectively, which is an analogy to human FKBP38 (Geisler and Hegedus, 2020).…”

The incredible diversity of structures and functions of ABC transporters

“…However, translation of biochemical findings to clinically relevant concepts is not always straightforward. Structural alterations may not only result in defects of transporter or channel activity, but also result in improper folding, derailed trafficking, and degradation [27]. The clinical relevance of these alterations in drug metabolism, cancer multidrug resistance, and impaired physiology is also discussed [28].…”