Evidence for a dipeptide porter in the lysosome membrane

Bird, Susan J.; Lloyd, John

doi:10.1016/0005-2736(90)90353-p

Cited by 20 publications

(7 citation statements)

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“…Indeed a rapid reported hydrolysis rate proves a good predictor of lytic ability. Thus our results are consistent with two elements of Goldman's hypothesis, namely that uptake into and hydrolysis within lysosomes are integral to the lytic ability (4) 70 f 2 (4) 45 f 4 (6) 53 i 4 (6) 36 f 4 (4) 47 i 2 (4) 10*3(3) 12 f 2 (3)…”

Section: Discussionsupporting

confidence: 89%

Mechanism of lysosome rupture by dipeptides

Bird

Lloyd

1995

Cell Biochemistry & Function

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Low concentrations of some neutral dipeptides, such as L-Ala-L-Ala, rapidly disrupt rat liver lysosomes. The phenomenon has been attributed to an osmotic imbalance generated by the production of amino acids in the lysosome by lysosomal dipeptidase activity. This hypothesis is challenged by testing several pairs of dipeptides available in both D- and L-forms and a range of dipeptides whose susceptibility to lysosomal dipeptidase activity is known. A good correlation was found between the lytic ability of dipeptides and their capacity to cross the lysosome membrane and be hydrolysed by lysosomal dipeptidase. The osmotic-imbalance hypothesis is critically evaluated in the light of the results and of recent information concerning the carrier-mediated transport of amino acids and dipeptides across the lysosome membrane. It is concluded that intralysosomal generation of amino acids remains the most plausible explanation of the lytic activity of dipeptides, and that the dipeptide porter(s) in the lysosome membrane must have higher Km than the amino acid porters.

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Section: Discussionsupporting

confidence: 89%

Mechanism of lysosome rupture by dipeptides

Bird

Lloyd

1995

Cell Biochemistry & Function

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“…Thamotharan et al showed that when lysosomal membrane vesicles were incubated with the dipeptide Gly-Gln, the uptake was saturable and proton-dependent (14). The lysosomal membrane vesicles were also able to take up GlyGly, Gly-Ala, or the tripeptides MMK, AYK, and RCK (15,16). In 3H-ribonuclease-loaded lysosome preparations, 8 to 18 amino acid peptides were detected in the release medium (15).…”

Section: Subcellular Localization Of Hpept1-gfp Fusion Proteinmentioning

confidence: 99%

Drug inhibition of Gly-Sar uptake and hPepT1 localization using hPepT1-GFP fusion protein

et al. 2001

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“…Various regulatory mechanisms of lysosomal amino acid transport have been discovered (Abu-Remaileh et al, 2017; Bandyopadhyay et al, 2022; Leray et al, 2021), and transporter structures have been characterized (Guo et al, 2022; Lei et al, 2018; Lobel et al, 2022). In contrast, lysosomal peptide transporters have received much less attention, although it has been known for decades that in lysosomes, specific peptides are not completely proteolytically degraded to single amino acids and that lysosomal peptide transporters must exist (Bird and Lloyd, 1990; Coffey and De Duve, 1968; Isenman and Dice, 1993; Thamotharan et al, 1997). Two members of the POT family, PHT1 (SLC15A4) and PHT2 (SLC15A3) localize to lysosomes and endosomes (Bockman et al, 1997; Kobayashi et al, 2014; Nakamura et al, 2014) and have been experimentally shown to transport carnosine, MDP, tri-DAP, Gly-Sar by PHT1 and His-Leu by PHT2 (Dong et al, 2023; Oppermann et al, 2019; Sakata et al, 2001; Wang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

MFSD1 in complex with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes

Jungnickel,

Guelle,

Iguchi

et al. 2023

Preprint

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SummaryLysosomal degradation of macromolecules in lysosomes produces diverse small metabolites exported by specific transporters for reuse in biosynthetic pathways. Here, we deorphanized the Major Facilitator Superfamily Domain Containing 1 (MFSD1) protein, which forms a tight complex with the Glycosylated Lysosomal Membrane Protein (GLMP) in the lysosomal membrane. Untargeted metabolomics analysis of MFSD1-deficient mouse lysosomes revealed an increase in cationic dipeptides. Purified MFSD1 selectively bound diverse dipeptides, while electrophysiological, isotope tracer, and fluorescence-based studies inXenopusoocytes and proteoliposomes showed that MFSD1/GLMP acts as a uniporter for cationic and neutral dipeptides. Cryo-EM structure of the dipeptide-bound MFSD1/GLMP complex in outward-open conformation characterized the heterodimer interface and, in combination with molecular dynamics simulations, provided a structural basis for its selectivity towards diverse dipeptides. Together, our data identify MFSD1 as a general lysosomal dipeptide uniporter, providing an alternative route to recycle lysosomal proteolysis products when lysosomal amino acid exporters are overloaded.

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Evidence for a dipeptide porter in the lysosome membrane

Cited by 20 publications

References 5 publications

Mechanism of lysosome rupture by dipeptides

Mechanism of lysosome rupture by dipeptides

Drug inhibition of Gly-Sar uptake and hPepT1 localization using hPepT1-GFP fusion protein

MFSD1 in complex with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes

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