Christopher G. Burd's research while affiliated with Yale University and other places
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Publications (90)
Sphingomyelin is a dominant sphingolipid in mammalian cells. Its production in the trans- Golgi traps cholesterol synthesized in the ER to promote formation of a sphingomyelin/sterol gradient along the secretory pathway. This gradient marks a fundamental transition in physical membrane properties that help specify organelle identify and function. W...
The trans Golgi network must coordinate sorting and secretion of proteins and lipids to intracellular organelles and the plasma membrane. During polarization of epithelial cells, changes in the lipidome and the expression and distribution of proteins contribute to the formation of apical and basolateral plasma membrane domains. Previous studies uti...
The most abundant sphingolipid of the plasma membrane (PM), sphingomyelin (SM), binds to cholesterol in a manner dependent on the structure of fatty acids in the SM, and it is a major determinant of the cholesterol content of the PM. Synthesis of SM in the Golgi apparatus produces an mol-equivalent of diacylglycerol (DAG), a signaling lipid implica...
Lysosomes are vital organelles vulnerable to injuries from diverse materials. Failure to repair or sequester damaged lysosomes poses a threat to cell viability. Here we report that cells exploit a sphingomyelin-based lysosomal repair pathway that operates independently of ESCRT to reverse potentially lethal membrane damage. Various conditions pertu...
Sphingomyelin is a dominant sphingolipid in mammalian cells. Its production in the trans-Golgi traps cholesterol synthesized in the ER to promote formation of a sphingomyelin/sterol gradient along the secretory pathway. This gradient marks a fundamental transition in physical membrane properties that help specify organelle identify and function. We...
The Golgi functions principally in the biogenesis and trafficking of glycoproteins and lipids. It is compartmentalized into multiple flattened adherent membrane sacs termed cisternae, which each contain a distinct repertoire of resident proteins, principally enzymes that modify newly synthesized proteins and lipids sequentially as they traffic thro...
Cisternae of the Golgi apparatus adhere to each other to form stacks, which are aligned side by side to form the Golgi ribbon. Two proteins, GRASP65 and GRASP55, previously implicated in stacking of cisternae, are shown to be required for the formation of the Golgi ribbon.
Lysosomes are vital organelles vulnerable to injuries from diverse materials. Failure to repair or sequester damaged lysosomes poses a threat to cell viability. Here we report that cells exploit a sphingomyelin-based lysosomal repair pathway that operates independently of ESCRT to reverse potentially lethal membrane damage. Various conditions pertu...
Phosphatidylethanolamine is an abundant component of most cellular membranes whose physical and chemical properties modulate multiple aspects of organelle membrane dynamics. An evolutionarily ancient mechanism for producing phosphatidylethanolamine is to decarboxylate phosphatidylserine and the enzyme catalyzing this reaction, phosphatidylserine de...
Phosphatidylethanolamine is an abundant component of most cellular membranes whose physical and chemical properties modulate multiple aspects of organelle membrane dynamics. An evolutionarily ancient mechanism for producing phosphatidylethanolamine is to decarboxylate phosphatidylserine and the enzyme catalyzing this reaction, phosphatidylserine de...
Retromer orchestrates the selection and export of integral membrane proteins from the endosome via retrograde and plasma membrane recycling pathways. Long standing hypotheses regarding the Retromer sorting mechanism posit that oligomeric interactions between Retromer and associated accessory factors on the endosome membrane drives clustering of Ret...
Retromer is a protein sorting device that orchestrates the selection and export of integral membrane proteins from the endosome via retrograde and plasma membrane recycling pathways. Long standing hypotheses regarding the Retromer sorting mechanism posit that oligomeric interactions between Retromer and associated accessory factors on the endosome...
In the secretory pathway, budding of vesicular transport carriers from the trans-Golgi network (TGN) must coordinate specification of lipid composition with selection of secreted proteins. We elucidate a mechanism of soluble protein cargo sorting into secretory vesicles with a sphingomyelin-rich membrane; the integral membrane proteoglycan Syndecan...
The endosomal system functions as a network of protein and lipid sorting stations that receives molecules from endocytic and secretory pathways and directs them into a lysosome targeting pathway, or an endosome export pathway that acts in a retrograde trafficking pathway or plasma membrane recycling pathways. Retrograde trafficking pathways describ...
Synaptobrevin/VAMP2 is an essential SNARE protein that has been extensively studied in its role in synaptic vesicle fusion. However, sorting and trafficking of VAMP2 within the endosomal system is not well understood. Here, we use the yeast VAMP2 homologue Snc1 to investigate the pathways and signals required for endocytic trafficking. We identify...
How the principal functions of the Golgi apparatus-protein processing, lipid synthesis, and sorting of macromolecules-are integrated to constitute cargo-specific trafficking pathways originating from the trans-Golgi network (TGN) is unknown. Here, we show that the activity of the Golgi localized SPCA1 calcium pump couples sorting and export of secr...
Sphingolipids are structural components of organelle membranes that also participate in signal transduction pathways. Complex sphingolipids are trafficked from their site of synthesis in organelles of the early secretory pathway to the Golgi apparatus, the plasma membrane, and the endo‐lysosomal system. We have developed fluorescence microscopy–bas...
Cell-penetrating peptides (CPPs) are short protein segments that can transport cargos into cells. Although CPPs are widely studied as potential drug delivery tools, their role in normal cell physiology is poorly understood. Early during infection, the L2 capsid protein of human papillomaviruses binds retromer, a cytoplasmic trafficking factor requi...
Cargo-selective and non-selective autophagy pathways employ a common core autophagy machinery that directs biogenesis of an autophagosome which eventually fuses with the lysosome to mediate turnover of macromolecules. In yeast ( Saccharomyces cerevisiae) cells, several selective autophagy pathways fail in cells lacking the dimeric Snx4/Atg24 and At...
We describe a regulatory mechanism that controls the activity of retromer, an evolutionarily conserved sorting device that orchestrates cargo export from the endosome. A spontaneously arising mutation that activates the yeast (Saccharomyces cerevisiae) CDC25 family phosphatase, Mih1, results in accelerated turnover of a subset of endocytosed plasma...
The yeast SNX4 sub-family of SNX-BAR proteins, Snx4/Atg24, Snx41, and Atg20/Snx42, are required for endocytic recycling and selective autophagy. Here we show that Snx4 forms two functionally distinct heterodimers: Snx4-Atg20 and Snx4-Snx41. Each heterodimer coats an endosome-derived tubule that mediates retrograde sorting of distinct cargo; the v-S...
The large GTPase dynamin is the first protein shown to catalyze membrane fission. Dynamin and its related proteins are essential to many cell functions, from endocytosis to organelle division and fusion, and it plays a critical role in many physiological functions such as synaptic transmission and muscle contraction. Research of the past three deca...
Significance
The biochemical reactions that drive cellular life are housed in distinct membrane enclosed compartments known as organelles. Whereas proteins targeting to different organelles are well developed, little is known regarding how lipids are sorted to different organelles. We engineered a protein from a marine organism into a fluorescent “...
1 DepartmentofGenetics,YaleSchoolofMedicine,NewHaven,Connecticut,UnitedStatesofAmerica,2 DepartmentofMolecularBiophysicsandBiochemistry,YaleUniversity,NewHaven,Connecticut,UnitedStatesofAmerica,3 DepartmentofTherapeuticRadiology,YaleSchoolofMedicine,NewHaven,Connecticut,UnitedStatesofAmerica,4 YaleCancerCenter,NewHaven,Connecticut,UnitedStatesofAme...
Sorting of macromolecules within the endosomal system is vital for physiological control of nutrient homeostasis, cell motility, and proteostasis. Trafficking routes that export macromolecules from the endosome via vesicle and tubule transport carriers constitute plasma membrane recycling and retrograde endosome-to-Golgi pathways. Proteins of the s...
Author Summary
The human papillomaviruses are important carcinogens, but little is known about how these non-enveloped viruses traffic to the nucleus, the site of genome replication. We use imaging, biochemical, and genetic techniques to show that a multi-subunit intracellular trafficking machine known as retromer binds directly to the L2 minor cap...
Sac1 is a phosphoinositide phosphatase of the endoplasmic reticulum and Golgi apparatus that controls organelle membrane composition principally via regulation of phosphatidylinositol 4-phosphate signaling. We present a characterization of the structure of the N-terminal portion of yeast Sac1, containing the conserved Sac1 homology domain, in compl...
Retromer is an endosomal sorting device that orchestrates capture and packaging of cargo into transport carriers coated with sorting nexin BAR domain proteins (SNX-BARs). We report that fission of retromer SNX-BAR-coated tubules from yeast endosomes is promoted by Vps1, a dynamin-related protein that localizes to endosomes decorated by retromer SNX...
The endosomal network comprises an interconnected network of membranous compartments whose primary function is to receive, dissociate, and sort cargo that originates from the plasma membrane and the biosynthetic pathway. A major challenge in cell biology is to achieve a thorough molecular description of how this network operates, and in so doing, h...
Plasma membrane PI4P helps determine the identity of this membrane and plays a key role in signal transduction as the precursor of PI(4,5)P2 and its metabolites. Here, we report the atomic structure of the protein scaffold that is required for the plasma membrane localization and function of Stt4/PI4KIIIα, the PI 4-kinase responsible for this PI4P...
Significance
The endosomal system is a network of organelles that play key roles in nutrient uptake, protein and lipid sorting, and signal transduction. Integral membrane proteins are delivered to endosomes via trafficking from the plasma membrane and the secretory pathway, and many of these proteins are then returned from the endosome for reuse. T...
Vesicle-mediated protein transport between organelles of the secretory and endocytic pathways is strongly influenced by the composition and organization of membrane lipids. In budding yeast, protein transport between the trans-Golgi network (TGN) and early endosome (EE) requires Drs2, a phospholipid translocase in the type IV P-type ATPase family....
The retromer complex, composed of sorting nexin subunits and a Vps26/Vps29/Vps35 trimer, mediates sorting of retrograde cargo from the endosome to the trans-Golgi network. The retromer trimer subcomplex is an effector of Rab7 (Ypt7 in yeast). Whereas endosome targeting of human retromer has been shown to require Rab7-GTP, targeting of yeast retrome...
In the Golgi apparatus, lipid homeostasis pathways are coordinated with the biogenesis of cargo transport vesicles by phosphatidylinositol 4-kinases (PI4Ks) that produce phosphatidylinositol 4-phosphate (PtdIns4P), a signaling molecule that is recognized by downstream effector proteins. Quantitative analysis of the intra-Golgi distribution of a Ptd...
Bidirectional traffic between the Golgi apparatus and the endosomal system sustains the functions of the trans-Golgi network (TGN) in secretion and organelle biogenesis. Export of cargo from the TGN via anterograde trafficking pathways depletes the organelle of sorting receptors, processing proteases, SNARE molecules, and other factors, and these a...
Phosphatidylinositol 4-kinases (PI4Ks) regulate vesicle-mediated export from the Golgi apparatus via phosphatidylinositol 4-phosphate (PtdIns4P) binding effector proteins that control vesicle budding reactions and regulate membrane dynamics. Evidence has emerged from the characterization of Golgi PI4K effectors that vesicle budding and lipid dynami...
Parkinson's disease is the most common neurodegenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson's disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently...
Targeting and retention of resident integral membrane proteins of the Golgi apparatus underly the function of the Golgi in glycoprotein and glycolipid processing and sorting. In yeast, steady-state Golgi localization of multiple mannosyltransferases requires recognition of their cytosolic domains by the peripheral Golgi membrane protein Vps74, an o...
The FYVE domain associates with phosphatidylinositol 3-phosphate [PtdIns(3)P] in membranes of early endosomes and penetrates bilayers. Here, we detail principles of membrane anchoring and show that the FYVE domain insertion into PtdIns(3)P-enriched membranes and membrane-mimetics is substantially increased in acidic conditions. The EEA1 FYVE domain...
Endocytosed proteins are either delivered to the lysosome to be degraded or are exported from the endosomal system and delivered to other organelles. Sorting of the Saccharomyces cerevisiae reductive iron transporter, composed of the Fet3 and Ftr1 proteins, in the endosomal system is regulated by available iron; in iron-starved cells, Fet3-Ftr1 is...
The mechanism of glycosyltransferase localization to the Golgi apparatus is a long-standing question in secretory cell biology. All Golgi glycosyltransferases are type II membrane proteins with small cytosolic domains that contribute to Golgi localization. To date, no protein has been identified that recognizes the cytosolic domains of Golgi enzyme...
Aggregated alpha-synuclein (alpha-syn) fibrils form Lewy bodies (LBs), the signature lesions of Parkinson's disease (PD) and related synucleinopathies, but the pathogenesis and neurodegenerative effects of LBs remain enigmatic. Recent studies have shown that when overexpressed in Saccharomyces cerevisiae, alpha-syn localizes to plasma membranes and...
The Saccharomyces cerevisiae high-affinity copper transporter, Ctr1p, mediates cellular uptake of Cu(I). We report that when copper (50 microm CuSO(4)) is added to the growth medium of copper-starved cells, Ctr1p is rapidly internalized by endocytosis, delivered to the lumen of the lysosome-like vacuole and slowly degraded by vacuolar proteases. Th...
Amajor function of the endocytic system is the sorting of cargo to various organelles. Endocytic sorting of the yeast reductive iron transporter, which is composed of the Fet3 and Ftr1 proteins, is regulated by available iron. When iron is provided to iron-starved cells, Fet3p-Ftr1p is targeted to the lysosome-like vacuole and degraded. In contrast...
The Vam7p t-SNARE is an essential component of the vacuole fusion machinery that mediates membrane trafficking and protein sorting in yeast. Vam7p is recruited to vacuoles by its N-terminal PX domain that specifically recognizes PtdIns(3)P in the bilayers, however the precise mechanism of membrane anchoring remains unclear. Here we describe a molec...
Specific recognition of phosphatidylinositol 3-phosphate [PtdIns(3)P] by the FYVE domain targets cytosolic proteins to endosomal membranes during key signaling and trafficking events within eukaryotic cells. Here, we show that this membrane targeting is regulated by the acidic cellular environment. Lowering the cytosolic pH enhances PtdIns(3)P affi...
Rab GTPases are crucial regulators of organelle biogenesis, maintenance, and transport. Multiple Rabs are expressed in all cells, and each is localized to a distinct set of organelles, but little is known regarding the mechanisms by which Rabs are targeted to their resident organelles. Integral membrane proteins have been postulated to serve as rec...
tGolgin-1 (trans-Golgi p230, golgin-245) is a member of a family of large peripheral membrane proteins that associate with the trans-Golgi network (TGN) via a C-terminal GRIP domain. Some GRIP-domain proteins have been implicated in endosome-to-TGN transport but no function for tGolgin-1 has been described. Here, we show that tGolgin-1 production i...
ADP-ribosylation factor (Arf) GTP-binding proteins are among the best-characterized members of the Ras superfamily of GTPases, with well-established functions in membrane-trafficking pathways. A recent watershed of genomic and structural information has identified a family of conserved related proteins: the Arf-like (Arl) GTPases. The best-characte...
Intracellular signal transduction occurs through cascades of reactions involving dozens of proteins that transmit signals from the cell surface, through a crowded cellular environment filled with organelles and a filamentous cytoskeleton, to specific targets. Numerous signaling molecules are immobilized or transiently bound to the cytoskeleton, yet...
Myristoylation of ARF family GTPases is required for their association with Golgi and endosomal membranes, where they regulate protein sorting and the lipid composition of these organelles. The Golgi-localized ARF-like GTPase Arl3p/ARP lacks a myristoylation signal, indicating that its targeting mechanism is distinct from myristoylated ARFs. We dem...
A genetic interaction network containing�1000 genes and�4000 interactions
was mapped by crossing mutations in 132 different query genes into a set of
�4700 viable gene yeast deletion mutants and scoring the double mutant
progeny for fitness defects.Network connectivity was predictive of function
because interactions often occurred among functionall...
Polarized growth in Saccharomyces cerevisiae is thought to occur by the transport of post-Golgi vesicles along actin cables to the daughter cell, and the subsequent fusion of the vesicles with the plasma membrane. Previously, we have shown that Msb3p and Msb4p genetically interact with Cdc42p and display a GTPase-activating protein (GAP) activity t...
The majority of Rab proteins are posttranslationally modified with two geranylgeranyl lipid moieties that enable their stable association with membranes. In this study, we present evidence to demonstrate that there is a specific lipid requirement for Rab protein localization and function. Substitution of different prenyl anchors on Rab GTPases does...
Golgins are Golgi-localized proteins present in all molecularly characterized eukaryotes that function in Golgi transport and maintenance of Golgi structure. Some peripheral membrane Golgins, including the yeast Imh1 protein, contain the recently described GRIP domain that can independently mediate Golgi localization by an unknown mechanism. To ide...
Signaling by phosphatidylinositol 3-kinases (PI3Ks) is often mediated by proteins which bind PI3K products directly and are localized to intracellular membranes rich in PI3K products. The FYVE finger domain binds with high specificity to PtdIns3P and proteins containing this domain have been shown to be important components of diverse PI3K signalin...
Rab GTPases are localized to distinct subsets of organelles within the cell, where they regulate SNARE-mediated membrane trafficking
between organelles. One factor required for Rab localization and function is Rab GDP dissociation inhibitor (GDI), which is
proposed to recycle Rab after vesicle fusion by extracting Rab from the membrane and loading...
Mutations in the NPC1 gene cause Niemann-Pick type C disease, which is characterized by the accumulation of free cholesterol and other lipids in lysosomes. The NPC1 glycoprotein is located in a late endosomal compartment that transiently interacts with lysosomes. To identify factors regulating NPC1 expression and action, we analyzed the function of...
The use of the Aequoreu Victoria green fluorescent protein (GFP) as a real-time molecular tag to study protein localization and dynamics has had a major impact in yeast cell biology. The experimental possibilities are explored that are manifested by integrating GFP-based technologies with the broad array of existing genetic and molecular biology ye...
Recognition of phosphatidylinositol 3-phosphate (Ptdlns(3)P) is crucial for a broad range of cellular signaling and membrane trafficking events regulated by phosphoinositide (PI) 3-kinases. PtdIns(3)P binding by the FYVE domain of human early endosome autoantigen 1 (EEA1), a protein implicated in endosome fusion, involves two beta hairpins and an a...
Guanine nucleotide dissociation inhibitor (GDI) is an essential protein required for the recycling of Rab GTPases mediating
the targeting and fusion of vesicles in the exocytic and endocytic pathways. Using site-directed mutagenesis of yeastGDI1, we demonstrate that amino acid residues required for Rab recognition in vitro are critical for function...
The vacuolar protein sorting (VPS) pathway of Saccharomyces cerevisiae mediates transport of vacuolar protein precursors from the late Golgi to the lysosome-like vacuole. Sorting of some vacuolar proteins occurs via a prevacuolar endosomal compartment and mutations in a subset of VPS genes (the class D VPS genes) interfere with the Golgi-to-endosom...
Analysis of membrane transport in the yeast Saccharomyces cerevisiae continues to provide important insights into the molecular mechanisms that direct endocytic and lysosomal sorting pathways in eukaryotic cells. Recent findings include the identification of two novel endomembrane transport pathways, a Golgi-to-vacuole biosynthetic pathway requirin...
The transport of newly synthesized proteins through the vacuolar protein sorting pathway in the budding yeast Saccharomyces cerevisiae requires two distinct target SNAP receptor (t-SNARE) proteins, Pep12p and Vam3p. Pep12p is localized to the pre-vacuolar endosome and its activity is required for transport of proteins from the Golgi to the vacuole...
Phosphoinositide 3-kinases (PI(3)K) are important regulators of receptor signaling cascades and intracellular membrane trafficking. To date, no protein domain has been identified that binds specifically to Ptdlns(3)P and thereby recruits/activates downstream effectors of Ptdlns(3)P signaling. Using an in vivo assay in yeast that detects Vps34 PI(3)...
The vacuolar protein-sorting (VPS) pathway of Saccharomyces cerevisiae mediates localization of proteins from the trans-Golgi to the vacuole via a prevacuolar endosome compartment. Mutations in class D vacuolar protein-sorting (vps) genes affect vesicle-mediated Golgi-to-endosome transport and result in secretion of vacuolar proteins. Temperature-s...
More than 40 vacuolar protein sorting (vps) mutants have been identified which secrete proenzyme forms of soluble vacuolar hydrolases to the cell surface. A subset of these mutants has been found to show selective defects in the sorting of two vacuolar membrane proteins. Under non-permissive conditions, vps45tsf (SEC1 homolog) and pep12/vps6tsf (en...
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Vesicle-mediated membrane traffic has long been considered to be a constitutive process that is not burdened by layers of regulation. This contrasts with transmembrane signalling systems at the plasma membrane which relay information (i.e. extracellular stimuli) from the cell surface to the cytoplasm via a myriad of different protein-protein intera...
In the yeast Saccharomyces cerevisiae, mutations in vacuolar protein sorting (VPS) genes result in secretion of proteins normally localized to the vacuole. Characterization of the VPS pathway has provided considerable insight into mechanisms of protein sorting and vesicle-mediated intracellular transport. We have cloned VPS9 by complementation of t...
The hnRNP C proteins (C1/C2) are tenacious nuclear pre-mRNA-binding proteins that belong to the large RNP motif family of RNA-binding proteins. This motif identifies an RNA-binding domain (RBD) that consists of a four-stranded antiparallel beta-sheet packed against two alpha-helices. Despite considerable information on the structure of the hnRNP C...
In eukaryotic cells, a multitude of RNA-binding proteins play key roles in the posttranscriptional regulation of gene expression.
Characterization of these proteins has led to the identification of several RNA-binding motifs, and recent experiments have
begun to illustrate how several of them bind RNA. The significance of these interactions is refl...
The poly(A)-binding protein (PABP) binds to the messenger (mRNA) 3'-poly(A) tail found on most eukaryotic mRNAs and together with the poly(A) tail has been implicated in governing the stability and the translation of mRNA. In order to further understand the role of the PABP in these processes, we have undertaken a detailed analysis of the cellular...
Pre-mRNA is processed as a large complex of pre-mRNA, snRNPs and pre-mRNA binding proteins (hnRNP proteins). The significance of hnRNP proteins in mRNA biogenesis is likely to be reflected in their RNA binding properties. We have determined the RNA binding specificity of hnRNP A1 and of each of its two RNA binding domains (RBDs), by selection/ampli...
The isolation of hnRNP complexes has identified many new proteins and their characterization has led to the identification of several motifs that are important for RNA binding. These motifs are present in a wide variety of proteins including splicing factors, ribosomal proteins, and several proteins of unknown function. These findings have blurred...
We have previously described a developmentally regulated mRNA in maize that accumulates in mature embryos and is involved in a variety of stress responses in the plant. The sequence of the encoded 16 kDa protein (MA 16) predicts that it is an RNA-binding protein, since it possesses a ribonucleoprotein consensus sequence-type RNA-binding domain (CS-...