GSAP modulates γ-secretase specificity by inducing conformational change in PS1

Wong, Eitan; Liao, George P.; Chang, Jerry C.; Xu, Peng; Li, Yueming; Greengard, Paul

doi:10.1073/pnas.1820160116

Cited by 50 publications

(46 citation statements)

References 30 publications

(65 reference statements)

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“…Cell membrane preparation and γ-secretase assays were described previously 75–78 . Briefly, cells were harvested from T75 flask 90% confluency and collected by centrifuge (800 g, 10 min).…”

Section: Methodsmentioning

confidence: 99%

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Kleffman

Levinson

Wong

et al. 2019

Preprint

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26Brain metastasis is a significant cause of morbidity and mortality in multiple cancer 27 types and represents an unmet clinical need. The mechanisms that mediate metastatic 28 cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the 29 highest rate of brain metastasis among common cancer types, is an ideal model to 30 study how cancer cells adapt to the brain parenchyma. We performed unbiased 31 proteomics analysis of melanoma short-term cultures, a novel model for the study of 32 brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative 33 pathologies are differentially expressed in melanoma cells explanted from brain 34 metastases compared to those derived from extracranial metastases. This raised the 35 exciting hypothesis that molecular pathways implicated in neurodegenerative disorders 36 are critical for metastatic adaptation to the brain. 37 38Here, we show that melanoma cells require amyloid beta (Ab), a polypeptide heavily 39 implicated in Alzheimer's disease, for growth and survival in the brain parenchyma. 40Melanoma cells produce and secrete Ab, which activates surrounding astrocytes to a 41 pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that 42 pharmacological inhibition of Ab decreases brain metastatic burden. 43 44Our results reveal a mechanistic connection between brain metastasis and Alzheimer's 45 disease -two previously unrelated pathologies, establish Ab as a promising therapeutic 46 target for brain metastasis, and demonstrate suppression of neuroinflammation as a 47 critical feature of metastatic adaptation to the brain parenchyma. 48 49 3 Main 50 51Brain metastasis is the most common form of adult intracranial malignancy 1 and results 52 in severe morbidity and mortality. 40-75% of Stage IV melanoma patients develop brain 53 metastasis 2,3 , reflecting melanoma's striking ability to colonize the brain. Brain 54 metastases are less responsive than extracranial metastases to current cancer 55 therapies 4-6 , and the majority of patients succumb to disease in less than one year 7 . 56 Furthermore, patients with brain metastasis are often excluded from clinical trials and 57 urgently need new clinical options. In recent years, research has started to elucidate the 58 molecular mechanisms contributing to the multi-step process of brain metastasis. Most 59 findings have focused on cancer extravasation across the blood-brain barrier (BBB), 60 which cannot be leveraged therapeutically given that the vast majority of brain 61 metastasis patients will present with extravasated cancer cells at the time of cancer 62 diagnosis. The main bottleneck in the brain metastatic process has been shown to be 63 the successful expansion of a single cell in the brain parenchyma to form a macro-64 metastasis 8 . Recent studies have begun to demonstrate the role of the brain 65 microenvironment in this process. In particular, reactive astrocytes have been shown to 66 interact with cancer cells in the brain 9,10 and exhibit both pro-and anti-...

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Section: Methodsmentioning

confidence: 99%

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Kleffman

Levinson

Wong

et al. 2019

Preprint

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“…On the other hand, the intermediate and extended conformation are enriched by the PSEN1ΔE9 FAD mutation, which inhibits the auto-proteolysis of PSEN1 and affects the cleavage of Aβ [113]. Importantly, presence of interactors such as γ-secretase activating protein (GSAP) also affect the likelihood of PSEN1 to adopt a functional conformation, although its role as modulator of activity remains controversial [131,132]. These conformational states have also been shown in the MD simulation for PSEN2/γ-secretase [119].…”

Section: Structural Dynamics: What Do We Know So Far?mentioning

confidence: 99%

Contribution of the Presenilins in the cell biology, structure and function of γ-secretase

Escamilla-Ayala

Wouters

Sannerud

et al. 2020

Seminars in Cell & Developmental Biology

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Secretase cleavage is essential for many biological processes and its dysregulation is linked to disease, including cancer and Alzheimer's disease. Therefore, understanding the regulation of its activity is of major importance to improve drug design and develop novel therapeutics. γ-Secretase belongs to the family of intramembrane cleaving proteases (i-CLiPs), which cleaves its substrates in a process termed regulated intramembrane proteolysis (RIP). During RIP, type-I transmembrane proteins are first cleaved within their ectodomain by a sheddase and then within their transmembrane domain by γ-secretase. γ-Secretase is composed of four integral membrane proteins that are all essential for its function: presenilin (PSEN), anterior pharynx defective 1 (APH1), nicastrin (NCT) and presenilin enhancer 2 (PEN-2). Given the presence of two PSEN homologues (PSEN1 & 2) and several APH1 isoforms, a heterogeneity exists in cellular γ-secretase complexes. It is becoming clear that each of these complexes has overlapping as well as distinct biological characteristics. This review summarizes our current knowledge on complex formation, trafficking, subcellular localization, interactors and the structure of γ-secretase, with a focus, when possible or known, on the contribution of PSEN1 and PSEN2 herein.

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“…Schematic representation of the conditions in which GSMP triggers the attenuation of γ-secretase activity and selectivity. Cells possess a different type of γ-secretase complexes with variable levels of activities (PDB structure: 6IDF), which under certain cellular circumstances GSMP can bind and modify its activity and selectivity (clockwise): endoplasmic reticulum (ER) stress upregulate stress-associated ER protein 1 (SERP1) expression which binds and localize the γ-secretase complex to lipid rafts where amyloid precursor protein (APP) resides thus increasing APP cleavage but not Notch processing (Jung et al, 2020), hypoxic conditions stabilize Hif-1α which in turn binds to γ-secretase and increase its activity for Notch substrates (Villa et al, 2014), innate immune response and aging triggers the binding of interferon-induced transmembrane protein 3 (IFITM3) thus enhancing γ-secretase for APP but reducing Notch processing (Hur et al, 2020) and under unknown conditions GSAP attenuates γ-secretase activity solely towards APP but not Notch (Wong et al, 2019; Magenta-Nicastrin, Green-Presenilin, Blue-Aph-1 and Red-Pen-2). GSAP that is associated with AD, which might associate GSAP as a disease-related risk factor (Zhu et al, 2014;Perez et al, 2017).…”

Section: γ-Secretase Activating Protein (Gsap)mentioning

confidence: 99%

“…The notion that an abundant protease like γ-secretase must respond to changes in the environment has led to the hypothesis that a fraction of the γ-secretase complexes exist in a partially dormant state and can be activated and attenuated by binding of γ-secretase modulatory proteins (GSMPs; Figure 1 ). Numerous proteins had been identified to interact with the core complex and impact γ-secretase activity (Chen et al, 2006 ; Vetrivel et al, 2007 ; Gertsik et al, 2014 ; Villa et al, 2014 ; Wong et al, 2019 ; Hur et al, 2020 ; Jung et al, 2020 ). In this review article, we will focus on the recent progress GSMPs and their regulation.…”

Section: The Context-dependent γ-Secretase Modulatory Proteins (Gsmpsmentioning

confidence: 99%

“…However, the following study brought the mechanism of GSAP in γ-secretase regulation into question, reporting that while knockdown of GSAP reduces Aβ production in cells, it is not through the interaction with βCTF (Hussain et al, 2013 ). A later study revealed that GSAP modulates γ-secretase activity by altering the active site and subsequently enhancing APP processing while not affecting Notch processing (Wong et al, 2019 ). In the case of GSAP, the precise cellular cue that is responsible for its interaction with γ-secretase is unclear, but there is an SNP in GSAP that is associated with AD, which might associate GSAP as a disease-related risk factor (Zhu et al, 2014 ; Perez et al, 2017 ).…”

Section: γ-Secretase Activating Protein (Gsap)mentioning

confidence: 99%

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γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors

Wong

Frost

2020

Front. Aging Neurosci.

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Described as the “proteasome of the membrane” or the “scissors in the membrane,” γ-secretase has notoriously complicated biology, and even after decades of research, the full extent of its regulatory mechanism remains unclear. γ-Secretase is an intramembrane aspartyl protease complex composed of four obligatory subunits: Nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (Pen-2), and Anterior pharynx-defective-1 (Aph-1). γ-Secretase cleaves numerous type 1 transmembrane substrates, with no apparent homology, and plays major roles in broad biological pathways such as development, neurogenesis, and cancer. Notch and the amyloid precursor protein (APP) and are undoubtedly the best-studied γ-secretase substrates because of their role in cancer and Alzheimer’s disease (AD) and therefore became the focus of increasing studies as an attractive therapeutic target. The regulation of γ-secretase is intricate and involves the function of multiple cellular entities. Recently, γ-secretase modulatory proteins (GSMPs), which are non-essential subunits and yet modulate γ-secretase activity and specificity, have emerged as an important component in guiding γ-secretase. GSMPs are responsive to cellular and environmental changes and therefore, provide another layer of regulation of γ-secretase. This type of enzymatic regulation allows for a rapid and fine-tuning of γ-secretase activity when appropriate signals appear enabling a temporal level of regulation. In this review article, we discuss the latest developments on GSMPs and implications on the development of effective therapeutics for γ-secretase-associated diseases such as AD and cancer.

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GSAP modulates γ-secretase specificity by inducing conformational change in PS1

Cited by 50 publications

References 30 publications

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Contribution of the Presenilins in the cell biology, structure and function of γ-secretase

γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors

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