Crystal structure of the ligand‐free form of the Vps10 ectodomain of dimerized Sortilin at acidic <scp>pH</scp>

Yabe-Wada, Toshiki; Matsuba, Shintaro; Unno, Masaki; Onai, Nobuyuki

doi:10.1002/1873-3468.13181

Cited by 9 publications

(6 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The observation of somal size as a factor correlating to the amount of sortilin expression might be of functional relevance. Recent cell biology and in vivo studies have increasingly recognized the role of sortilin for protein sorting, trafficking and homeostasis in neurons (Allard et al, 2018; Hirst et al, 2018; Itoh et al, 2018; Paushter et al, 2018; Yabe-Wada et al, 2018). Neurons are unique relative to other bodily cells most prominently as they generate and transmit electronic impulses to communicate between each other.…”

Section: Discussionmentioning

confidence: 99%

Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain

Zhang

et al. 2019

Front. Neuroanat.

View full text Add to dashboard Cite

Sortilin is a member of the vacuolar protein sorting 10 protein (VPS10P) domain receptor family, which carries out signal transduction and protein transport in cells. Sortilin serves as the third, G-protein uncoupled, receptor of neurotensin that can modulate various brain functions. More recent data indicate an involvement of sortilin in mood disorders, dementia and Alzheimer-type neuropathology. However, data regarding the normal pattern of regional and cellular expression of sortilin in the human brain are not available to date. Using postmortem adult human brains free of neuropathology, the current study determined sortilin immunoreactivity (IR) across the entire brain. Sortilin IR was broadly present in the cerebrum and subcortical structures, localizing to neurons in the somatodendritic compartment, but not to glial cells. In the cerebrum, sortilin IR exhibited differential regional and laminar patterns, with pyramidal, multipolar and polymorphic neurons in cortical layers II–VI, hippocampal formation and amygdaloid complex more distinctly labeled relative to GABAergic interneurons. In the striatum and thalamus, numerous small-to-medium sized neurons showed light IR, with a small group of large sized neurons heavily labeled. In the midbrain and brainstem, sortilin IR was distinct in neurons at the relay centers of descending and ascending neuroanatomical pathways. Dopaminergic neurons in the substantia nigra, cholinergic neurons in the basal nuclei of Meynert and noradrenergic neurons in the locus coeruleus co-expressed strong sortilin IR in double immunofluorescence. In comparison, sortilin IR was weak in the olfactory bulb and cerebellar cortex, with the mitral and Purkinje cells barely visualized. A quantitative analysis was carried out in the lateral, basolateral, and basomedial nuclei of the amygdaloid complex, as well as cortical layers II–VI, which established a positive correlation between the somal size and the intensity of sortilin IR among labeled neurons. Together, the present study demonstrates a predominantly neuronal expression of sortilin in the human brain with substantial regional and cell-type variability. The enriched expression of sortilin in pyramidal, dopaminergic, noradrenergic and cholinergic neurons suggests that this protein may be particularly required for signal transduction, protein trafficking and metabolic homeostasis in populations of relatively large-sized projective neurons.

show abstract

Section: Discussionmentioning

confidence: 99%

Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain

Zhang

et al. 2019

Front. Neuroanat.

View full text Add to dashboard Cite

show abstract

“…Ligands tend to show high affinity for sortilin at neutral pH but have a reduced or a complete loss of affinity at acidic pH ( 1 , 119 , 137 , 167 , 171 ), consistent with release of ligands in secretory granules or late endosomes. Recent reports by several groups have revealed that low pH triggers sortilin to undergo a conformational change and dimerize, causing the collapse of the binding site in the tunnel of the β-propeller and release of the ligand ( 92 , 172 , 173 , 174 ) ( Fig. 3 ).…”

Section: Structure and Function Of Sortilinmentioning

confidence: 99%

Sorting through the extensive and confusing roles of sortilin in metabolic disease

Mitok

Keller

Attie

2022

Journal of Lipid Research

View full text Add to dashboard Cite

“…The functions of sortilin in the exocytic trafficking of IFN-α was demonstrated in plasmacytoid dendritic cells (pDCs), known to secrete IFN-α (Yabe-Wada et al, 2016). This IFN trafficking depends on the dimerization of the sortilin ectodomain in acidic pH conditions encountered in the RE and TGN (Yabe-Wada et al, 2018). Through TLR9 activation, IFN-α release depends on sortilin and is diminished in sortilin-inactivated pDCs, without affecting its RNA transcription.…”

Section: Sortilin Sorla and Inflammationmentioning

confidence: 99%

Regulatory Roles of Sortilin and SorLA in Immune-Related Processes

et al. 2019

View full text Add to dashboard Cite

Sortilin, also known as Neurotensin Receptor-3, and the sorting-related receptor with type-A repeats (SorLA) are both members of the Vps10p domain receptor family. Initially identified in CNS cells, they are expressed in various other cell types where they exert multiple functions. Although mostly studied for its involvement in Alzheimer’s disease, SorLA has recently been shown to be implicated in immune response by regulating IL-6-mediated signaling, as well as driving monocyte migration. Sortilin has been shown to act as a receptor, as a co-receptor and as an intra- and extracellular trafficking regulator. In the last two decades, deregulation of sortilin has been demonstrated to be involved in many human pathophysiologies, including neurodegenerative disorders (Alzheimer and Parkinson diseases), type 2 diabetes and obesity, cancer, and cardiovascular pathologies such as atherosclerosis. Several studies highlighted different functions of sortilin in the immune system, notably in microglia, pro-inflammatory cytokine regulation, phagosome fusion and pathogen clearance. In this review, we will analyze the multiple roles of sortilin and SorLA in the human immune system and how their deregulation may be involved in disease development.

show abstract

Crystal structure of the ligand‐free form of the Vps10 ectodomain of dimerized Sortilin at acidic pH

Cited by 9 publications

References 31 publications

Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain

Regional and Cellular Mapping of Sortilin Immunoreactivity in Adult Human Brain

Sorting through the extensive and confusing roles of sortilin in metabolic disease

Regulatory Roles of Sortilin and SorLA in Immune-Related Processes

Contact Info

Product

Resources

About