Learning from each other: ABC transporter regulation by protein phosphorylation in plant and mammalian systems

Abstract

The ABC (ATP-binding cassette) transporter family in higher plants is highly expanded compared with those of mammalians. Moreover, some members of the plant ABCB subfamily display very high substrate specificity compared with their mammalian counterparts that are often associated with multidrug resistance (MDR) phenomena. In this review we highlight prominent functions of plant and mammalian ABC transporters and summarize our knowledge on their post-transcriptional regulation with a focus on protein phosphorylation. A deeper comparison of regulatory events of human cystic fibrosis transmembrane conductance regulator (CFTR) and ABCB1 from the model plant Arabidopsis reveals a surprisingly high degree of similarity. Both physically interact with orthologues of the FK506-binding proteins (FKBPs) that chaperon both transporters to the plasma membrane in an action that seems to involve Hsp90. Further both transporters are phosphorylated at regulatory domains that connect both nucleotide-binding folds. Taken together it appears that ABC transporters exhibit an evolutionary conserved but complex regulation by protein phosphorylation, which apparently is, at least in some cases, tightly connected with protein-protein interactions (PPI).

A Critical View on ABC Transporters and Their Interacting Partners in Auxin Transport

“…Co-immunoprecipitation data revealed that blue light reduced ABCB19-TWD1 interaction, which is dependent on phot1 (Christie et al 2011). These data together support a model in which ABCB phosphorylation by AGC kinases, such as phot1 or PID, alters the chaperoning role of TWD1 on ABCB PM trafficking by reducing ABCB-TWD1 interaction (Aryal et al 2015). A similar mode of action has been suggested for CFTR/ABCC7 secretion that is dependent both on interaction with FKBP38 and phosphorylation of the regulatory R domain, the equivalent of the ABCB linker, by protein kinase A.…”

“…Two recent studies support the concept that members of the plant-specific AGC protein kinase family, orthologs of mammalian protein kinases A, C and G, regulate ABCBs involved in auxin transport (Aryal et al 2015): first, the AGC4 kinase, PHOTROPIN1 (phot1) was shown to interact with the NBDs of ABCB19 (but not with ABCB1). Co-expression in HeLa cells reduced ABCB19 activity, which was further accelerated by blue light irradiation.…”

“…Beside ABCB-PIN interactions, ABCB-mediated auxin transport has been shown to be regulated by physical interactions with regulatory components such as kinases and immunophilins (Aryal et al 2015). These PPIs apparently allow for a quick and economic regulation of ABCBs and were shown to have an impact on transport activity, trafficking and stability.…”

“…This chaperone function on ABCB transporters seems to be conserved as the mammalian ortholog, FKBP38, was described to promote ER to PM delivery of ABCC7/CFTR (cystic fibrosis transmembrane conductance regulator), a chloride channel whose loss of function is responsible for the genetic disease mucoviscidosis (Banasavadi-Siddegowda et al 2011, Aryal et al 2015. As for TWD1, for FKBP38-CFTR regulation an involvement of PPIase activity was discussed but never clearly demonstrated.…”

“…This makes a strict requirement of PINs for ABCB transport activity unlikely. On the other hand, it is well known that ABC transporters can, besides functioning as transporters and channels, also act as regulators of other secondary active transport systems, including channels (Spalding 2013, Aryal et al 2015. A prominent example for such a functional interaction is the sulfonylurea receptor (SUR; ABCC8/9) that associates with the potassium channel proteins Kir6.1 or Kir6.2 to form the ATP-sensitive potassium channel (Principalli et al 2015).…”