Lateral plasma membrane compartmentalization links protein function and turnover

Abstract

1 Biological membranes organize their proteins and lipids into nano-and microscale 2 patterns. In the yeast plasma membrane (PM) constituents segregate into a large number 3 of distinct domains. However, if and how this intricate patchwork contributes to 4 biological functions at the PM is still poorly understood. Here, we reveal an elaborate 5 interplay between PM compartmentalization, biochemical function and endocytic 6 turnover. Using the methionine permease Mup1 as model system we demonstrate that 7 this transporter segregates into PM clusters. Clustering requires sphingolipids, the 8 tetraspanner Nce102 and TORC2 signaling. Importantly, we show that during substrate 9 transport, a simple conformational change in Mup1 mediates rapid relocation into a 10 unique disperse network at the PM. Clustered Mup1 is protected from turnover, 11whereas relocated Mup1 actively recruits the endocytic machinery thereby initiating its 12 own turnover. Our findings suggest that lateral compartmentalization provides an 13 important regulatory link between function and turnover of PM proteins. 14 15

Evolutionary journey and characterisation of a novel pan‐gene associated with beer strains of Saccharomyces cerevisiae

“…Furthermore, GFP fusions to other genes did not produce the same punctate patterns (W. Kricka and J. Fitzpatrick, personal communications). Interestingly, similar punctate staining patterns have been observed for other membrane‐associated proteins such as the methionine permease, Mup1p, and the arginine permease, Can1p (Busto et al, ). Several models such as the picket fence, the lipid raft, and hydrophobic mismatch have been proposed to explain the segregation of membrane‐associated proteins and lipids into such plasma membrane microdomains (Jensen & Mouritsen, ; Kusumi et al, ; Simons & Sampaio, ).…”

Functional patchworking at the plasma membrane

“…Additionally, a transport‐dependent ubiquitination mechanism was proposed for the glutamate receptor, GLT‐1, involving the beta‐arrestin‐1/Nedd4‐2 ubiquitination complex (Ibanez et al , ). Placed in the context of the study by Busto et al (), these examples collectively suggest that lateral compartmentalization of PM proteins plays an important role in controlling cellular physiology of all living cells.…”

“…In this issue, Busto and co‐workers carefully characterize the changes in lateral PM segregation exhibited by the methionine transporter Mup1 in response to nutrient availability (Fig ; Busto et al , ). They reveal how segregation of Mup1 is controlled and how its lateral distribution contributes to endocytosis and function of the transporter.…”

“… Lipids and proteins are not evenly distributed within the plasma membrane ( PM ), but instead segregate laterally into many specialized microdomains whose functional relevance is not clear. In this issue, Busto et al () demonstrate that substrate flux through a nutrient transporter drives the lateral relocation of the transporter between specific microdomains at the yeast PM , suggesting that regulating the lateral plasma membrane compartmentalization for individual proteins could be a general process for cellular response to environmental conditions. …”

Complementary α-arrestin - Rsp5 ubiquitin ligase complexes control selective nutrient transporter endocytosis in response to amino acid availability

“…the high affinity methionine transporter Mup1 as a model cargo because its regulation in response to 140 nutrient excess is well characterized (Busto et al, 2018, Lee et al, 2019, Gournas et al, 2018, Guiney 141 et al, 2016, Baile et al, 2019. Moreover, Mup1 is one of the most abundant PM proteins and it is easy 142 to follow its endocytosis and subsequent transport into the vacuole (Busto et al, 2018).…”