Tau is a microtubule-associated protein that plays a major role in Alzheimer's disease (AD) and other tauopathies. Recent reports indicate that, in the presence of crowding agents, tau can undergo liquid–liquid phase separation (LLPS), forming highly dynamic liquid droplets. Here, using recombinantly expressed proteins, turbidimetry, fluorescence microscopy imaging, and fluorescence recovery after photobleaching (FRAP) assays, we show that the divalent transition metal zinc strongly promotes this process, shifting the equilibrium phase boundary to lower protein or crowding agent concentrations. We observed no tau LLPS-promoting effect for any other divalent transition metal ions tested, including Mn2+, Fe2+, Co2+, Ni2+, and Cu2+. We also demonstrate that multiple zinc-binding sites on tau are involved in the LLPS-promoting effect and provide insights into the mechanism of this process. Zinc concentration is highly elevated in AD brains, and this metal ion is believed to be an important player in the pathogenesis of this disease. Thus, the present findings bring a new dimension to understanding the relationship between zinc homeostasis and the pathogenic process in AD and related neurodegenerative disorders.

The cell surfaces of many bacteria carry filamentous polypeptides termed adhesins that enable binding to both biotic and abiotic surfaces. Surface adherence is facilitated by the exquisite selectivity of the adhesins for their cognate ligands or receptors and is a key step in niche or host colonization and pathogenicity. Streptococcus gordonii is a primary colonizer of the human oral cavity and an opportunistic pathogen, as well as a leading cause of infective endocarditis in humans. The fibrillar adhesin CshA is an important determinant of S. gordonii adherence, forming peritrichous fibrils on its surface that bind host cells and other microorganisms. CshA possesses a distinctive multidomain architecture comprising an N-terminal target-binding region fused to 17 repeat domains (RDs) that are each ∼100 amino acids long. Here, using structural and biophysical methods, we demonstrate that the intact CshA repeat region (CshA_RD1–17, domains 1–17) forms an extended polymeric monomer in solution. We recombinantly produced a subset of CshA RDs and found that they differ in stability and unfolding behavior. The NMR structure of CshA_RD13 revealed a hitherto unreported all β-fold, flanked by disordered interdomain linkers. These findings, in tandem with complementary hydrodynamic studies of CshA_RD1–17, indicate that this polypeptide possesses a highly unusual dynamic transitory structure characterized by alternating regions of order and disorder. This architecture provides flexibility for the adhesive tip of the CshA fibril to maintain bacterial attachment that withstands shear forces within the human host. It may also help mitigate deleterious folding events between neighboring RDs that share significant structural identity without compromising mechanical stability.

Fucosylation of the innermost GlcNAc of N-glycans by fucosyltransferase 8 (FUT8) is an important step in the maturation of complex and hybrid N-glycans. This simple modification can dramatically affect the activities and half-lives of glycoproteins, effects that are relevant to understanding the invasiveness of some cancers, development of mAb therapeutics, and the etiology of a congenital glycosylation disorder. The acceptor substrate preferences of FUT8 are well-characterized and provide a framework for understanding N-glycan maturation in the Golgi; however, the structural basis of these substrate preferences and the mechanism through which catalysis is achieved remain unknown. Here we describe several structures of mouse and human FUT8 in the apo state and in complex with GDP, a mimic of the donor substrate, and with a glycopeptide acceptor substrate at 1.80–2.50 Å resolution. These structures provide insights into a unique conformational change associated with donor substrate binding, common strategies employed by fucosyltransferases to coordinate GDP, features that define acceptor substrate preferences, and a likely mechanism for enzyme catalysis. Together with molecular dynamics simulations, the structures also revealed how FUT8 dimerization plays an important role in defining the acceptor substrate-binding site. Collectively, this information significantly builds on our understanding of the core fucosylation process.

Type IV filaments (T4F), which are helical assemblies of type IV pilins, constitute a superfamily of filamentous nanomachines virtually ubiquitous in prokaryotes that mediate a wide variety of functions. The competence (Com) pilus is a widespread T4F, mediating DNA uptake (the first step in natural transformation) in bacteria with one membrane (monoderms), an important mechanism of horizontal gene transfer. Here, we report the results of genomic, phylogenetic, and structural analyses of ComGC, the major pilin subunit of Com pili. By performing a global comparative analysis, we show that Com pili genes are virtually ubiquitous in Bacilli, a major monoderm class of Firmicutes. This also revealed that ComGC displays extensive sequence conservation, defining a monophyletic group among type IV pilins. We further report ComGC solution structures from two naturally competent human pathogens, Streptococcus sanguinis (ComGCSS) and Streptococcus pneumoniae (ComGCSP), revealing that this pilin displays extensive structural conservation. Strikingly, ComGCSS and ComGCSP exhibit a novel type IV pilin fold that is purely helical. Results from homology modeling analyses suggest that the unusual structure of ComGC is compatible with helical filament assembly. Because ComGC displays such a widespread distribution, these results have implications for hundreds of monoderm species.

Much of our current knowledge of biological chemistry is founded in the structure-function relationship, whereby sequence determines structure that determines function. Thus, the discovery that a large fraction of the proteome is intrinsically disordered, while being functional, has revolutionized our understanding of proteins and raised new and interesting questions. Many intrinsically disordered proteins (IDPs) have been determined to undergo a disorder-to-order transition when recognizing their physiological partners, suggesting that their mechanisms of folding are intrinsically different from those observed in globular proteins. However, IDPs also follow some of the classic paradigms established for globular proteins, pointing to important similarities in their behavior. In this review, we compare and contrast the folding mechanisms of globular proteins with the emerging features of binding-induced folding of intrinsically disordered proteins. Specifically, whereas disorder-to-order transitions of intrinsically disordered proteins appear to follow rules of globular protein folding, such as the cooperative nature of the reaction, their folding pathways are remarkably more malleable, due to the heterogeneous nature of their folding nuclei, as probed by analysis of linear free-energy relationship plots. These insights have led to a new model for the disorder-to-order transition in IDPs termed “templated folding,” whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a cooperative folding.

Arrestin-1 is the arrestin family member responsible for inactivation of the G protein–coupled receptor rhodopsin in photoreceptors. Arrestin-1 is also well-known to interact with additional protein partners and to affect other signaling cascades beyond phototransduction. In this study, we investigated one of these alternative arrestin-1 binding partners, the glycolysis enzyme enolase-1, to map the molecular contact sites between these two proteins and investigate how the binding of arrestin-1 affects the catalytic activity of enolase-1. Using fluorescence quench protection of strategically placed fluorophores on the arrestin-1 surface, we observed that arrestin-1 primarily engages enolase-1 along a surface that is opposite of the side of arrestin-1 that binds photoactivated rhodopsin. Using this information, we developed a molecular model of the arrestin-1–enolase-1 complex, which was validated by targeted substitutions of charge-pair interactions. Finally, we identified the likely source of arrestin's modulation of enolase-1 catalysis, showing that selective substitution of two amino acids in arrestin-1 can completely remove its effect on enolase-1 activity while still remaining bound to enolase-1. These findings open up opportunities for examining the functional effects of arrestin-1 on enolase-1 activity in photoreceptors and their surrounding cells.

VOLUME 285 (2010) PAGES 13742–13747In Fig. 1E, passage 10, the splicing of a non-adjacent lane from the same immunoblot was not marked. This error has now been corrected and does not affect the results or conclusions of this work.jbc;295/16/5533/F1F1F1Figure 1E.

VOLUME 295 (2020) PAGES 3285–3300An incorrect graph was used in Fig. 5C. This error has now been corrected. Additionally, some of the statistics reported in the legend and text referring to Fig. 5C were incorrect. The F statistics for Fig. 5C should state Fken(3,16) = 7.454, p < 0.01; FCCCP(1,16) = 102.9, p < 0.0001; Finteraction(3,16) = 7.480, p < 0.01. This correction does not affect the results or conclusions of this work.jbc;295/17/5835/F5F1F5Figure 5C.

VOLUME 294 (2019) PAGES 2555–2568Due to publisher error, “150 l/mm” was changed to “150 liters/mm” in the second paragraph of the “Vibrational spectroscopy of samples” section under “Experimental Procedures.” The correct phrase should be “150 l/mm.”

VOLUME 295 (2020) PAGES 1898–1914Yichen Zhong's name was misspelled. The correct spelling is shown above.

VOLUME 295 (2020) PAGES 4079–4092There was an error in the abstract. “The pyridinium cation hampers uptake of OPs into the central nervous system (CNS)” should read as “The pyridinium cation hampers uptake into the central nervous system (CNS).”

VOLUME 287 (2012) PAGES 44508–44517In Fig. 1A, the wrong image for the control group was presented. The authors inadvertently cropped the control images in Fig. 1, A and E, from the same raw image. Fig. 1A has now been corrected and does not affect the results or conclusions of the work. The authors sincerely apologize for their mistake during figure preparation and for any inconvenience this may have caused readers.jbc;295/19/6781/F1F1F1Figure 1A.

The life cycle of malaria parasites in both their mammalian host and mosquito vector consists of multiple developmental stages that ensure proper replication and progeny survival. The transition between these stages is fueled by nutrients scavenged from the host and fed into specialized metabolic pathways of the parasite. One such pathway is used by Plasmodium falciparum, which causes the most severe form of human malaria, to synthesize its major phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Much is known about the enzymes involved in the synthesis of these phospholipids, and recent advances in genetic engineering, single-cell RNA-Seq analyses, and drug screening have provided new perspectives on the importance of some of these enzymes in parasite development and sexual differentiation and have identified targets for the development of new antimalarial drugs. This Minireview focuses on two phospholipid biosynthesis enzymes of P. falciparum that catalyze phosphoethanolamine transmethylation (PfPMT) and phosphatidylserine decarboxylation (PfPSD) during the blood stages of the parasite. We also discuss our current understanding of the biochemical, structural, and biological functions of these enzymes and highlight efforts to use them as antimalarial drug targets.

Many chemicals and cellular processes cause oxidative stress that can damage lipids, proteins, or DNA (1). To quickly sense and respond to this ubiquitous threat, organisms have evolved enzymes that neutralize harmful oxidants such as reactive oxygen species and electrophilic compounds (including xenobiotics and their breakdown products) in cells.These antioxidant enzymes include GSH S-transferase (GST),2 NADPH:quinone oxidoreductase 1, thioredoxin, hemeoxygenase-1, and others (2, 3). Many of these proteins are commonly expressed in cells exposed to oxidative stress.The antioxidant response element (ARE) is a major regulatory component of this cellular stress response. The ARE is a conserved, 11-nucleotide-long DNA motif present in the 5'-flanking regions of many genes encoding antioxidant proteins. The laboratory of Cecil Pickett (Fig. 1) at the Merck Frosst Centre for Therapeutic Research in Quebec discovered ARE, a finding reported in the early 1990s in two JBC papers recognized as Classics here (4, 5).jbc;295/12/3929/F1F1F1Figure 1.Cecil Pickett (pictured) and colleagues first described the ARE motif, present in the 5' regions of many genes whose expression is up-regulated by oxidative stress and xenobiotics. Photo courtesy of Cecil Pickett.ARE's discovery was spurred in large part by Pickett's career choice. After completing a PhD in biology and a 2-year postdoc at UCLA in the mid-1970s, he began to work in the pharmaceutical industry.Recruited to Merck in 1978 by its then head of research and development (and later CEO), Roy Vagelos, “I became interested in how drug-metabolizing enzymes were induced by various xenobiotics,” Pickett says.According to Pickett, Vagelos encouraged researchers at the company...

moving forward   me     moving     greatly       forward         me           moving             straightly               forward                 greatly             […]

It does not matter that he does not listen to you, That you’d rather he say your neck Is as graceful as an antelopes, Perhaps he’s not accustomed to lying. If he bought you an expensive phone you, Dropped in the bath the next day, would You, In yellow, Say he does not love you? […]

The place I used to visit, On bad days, With yoghurt and spoon, Is vacant. The leaves are raked, Into a neat pile, By the bench, And except for the newspaper, Blowing about in the wind, There is no-one here. The river beyond, Is a murky brown, Same as it’s always been, But, Over the […]

  Never mind steel, We are creating new materials, Carbon nano-tubes, poly-ceramics, Twirl a ball above your head, we are Building elevators into space, Stringing massage parlours around the earth, We are engineering ourselves, Computer worlds and, Selling real estate, we Are leaving the old people, Behind, Stained curtains and they are, Walking into forests, […]

  He is munching on nuts, vigorously, Utilising the muscles he has. He has wonderful eyes, Hawk eyes, Wide set and is, Now eating a banana with a plastic spoon. We both, have motioned for a waiter. He is masticating on a blob of Almond paste that he, Has scooped from a glass jar in […]

A brook runs through my Grandmas farm, That used to carry gold. My Grandpa -Benjamin- Did not yield the land, To the British, who wanted it dammed. In 1968, they took him in, To have his appendix removed, And Grandma never remarried. My Aunt Alice, Was a witch. She flew in on broomsticks We never […]

They say that Africans, Will have to fight for a place on the bus, So I am pulling out all the stops. I am burning incense and, Turning out closets, -exorcising demons- I am fumigating my life, Throwing out old clothes and, Trying to curry favour, -surely children were not meant for the streets, Nor […]

They’ve dimmed the lights getting ready to land service staff buckled down can’t see me pull out my camera, start clicking, clicking down the sci-fi lights, like some Twilight Zone episode where I’m holding my breath, waiting. Waiting for that thing You know, the thing the monster that tormented William Shatner, sitting in his youthful […]

When you are born, You know that you are, Here to change the world, And it is good, And it’s alright, To do your best. Then, You’re checking the curtains, Just in case, You run out of sunshine. -evocative short poetry-

I spoke French for thirteen years I say to him And he smiles. More cheese. Soft night yields to love, Rap is the only hard night sound, The White man is out of his depth, Even in French. He leans forward and whispers in my ear but, The first lie was mine. We’ll count them […]

“There are no terrorists in this location” Reads the title, In classic bold type, On Foolscap paper, On a dusty desk, Inside a police outpost in Isiolo. “The drilling rigs will make no difference to, The cows or the goats or the lives of the people, Who do not live here.” “The construction does not […]

the lone yellow pebble bore witness to the abduction that took place at midnight. The man was bound and gagged and led away as women wept. Keep me out of this one. Did you know that a bear needs twenty seven, Square miles of forest, to live? Keep me out of this one. The woman […]

Your thoughts are on pink. Pink elephants with floppy ears, Pink polcadot pillows, Pink rabbit-eared flip-flops with, Non-slip soles, Pink cereal, Pink hair bobbins, and The bright pink coffee shop, You would take her to, To apologise and review, Her new pink shoes. Why must everything be so loud? Bedraggled mops slop over, Tired hospital […]

You are – Living on the top floor, On a, Bunk-bed, In Finland, In a cultured, High-rise habitat, With cool, kitchen kettles, Where – You are not visited, Except by cameras, Or people taking your children away -evocative short poetry-

There’s a starfish in my tooth he says, A golden starfish nestling in the reef, Infecting the coral and, I’m in the deep blue ocean, Among sea creatures, Yellow and purple jellyfish, Undulating in the current, Stingrays swooping by, Luminescent seaweed hangs over caves, Like electric blue curtains, At a tatoo parlour. An octopus rakes […]

You would walk into a quiet house, In a quiet neighbourhood and, Take a young girl, Into the woods, And rape her, Leaving a father disfigured, You would, Take a husband, In the middle of the night, And break his legs, And electrocute him, Because he will not salute your Blown up image, You would, […]

How far would you travel from where you were born? She spends more on her dogs in one week, Than the government provides for those in trouble. She’s a naturally happy person. The mottled concrete walls of the council block she’s moved in to, Complement her pock-marked, pink skin. For a rich person, She’s ugly. […]

          Her legs will be amputated but, Non-collapsible items like, Book-shelves and fathers Can make a space to survive. -evocative short poetry-

Dance music, Damp heat and talk Drifts to halcyon days of, Seventies groove and Afro’s ruffled, In the political funk of, Freedom fighters and platform shoes, Cadillac language, Smooth and languid, Dripping off honey colored lips like, Melting chocolate… It’s a card trick, And we are mesmorised by, Furtive glances, Over fanned cards, Fascinated by […]

Here you are, In a long, low, valley, On a horse, under sweltering sky. A single trail runs East to West, As far as the eye can see. The sheep-skin bags, Slung low off the saddle, Are empty. Bandits rode into town last week, And made off with a couple of dreams, Now you must […]

A time will come, When you don’t even, Own your own body, On the side of the road, A full breakdown not a common, Puncture, Leave your heart, it’s broken, Total mechanical failure. What will you do? Trust what you have given? Love, a blue opinion? You have only what you spent. You think you […]

I am the gate keeper. Two flags gone Marking bodies where they fell, Manure, Useful, Two flags fleeing loose rounds, Auras, Fleeting, Bring your palm, I can read it now, Unhinged as I am, The last are, Making their way home. -evocative short poetry-

If you can’t hear on broadband, Don’t blame the bandwidth. Empty yourself of cares, If you can’t tune into radio waves, Don’t blame the radio. Make a habit of creating time. -evocative short poetry-

They are doing white Cars, Nice haircuts and, Broad Boulevards, They are doing slick radio Ads, Smooth charcoal voices, And Western music, Wrapped in Cashmere, Air-conditioned Kaftan’s catching the breeze, They are doing dark glasses like reflective buildings Perched on tight noses, Moving forward with morning talk shows in, Gleaming white cars, Elegant fingers prodding […]

I go to church and sit at the back while you tell me I’m going to hell I go to church and sit at the back while you announce the Dates for ‘Men’s Breakfast’ I go to church and sit at the back while you undress my sin, wanting to love me naked Stripped, beaten, […]

The broom slices across the floor,Cutting a precise path through the mess,Clean swathe through the valley,Creating mounds of discarded,Clothing,Pieces,Returning slowly to their original state while,Still holding plastic memories of the night out,A strong attempt at cleaning up,A fine start. Loose Birthday cards too, Steal up on you, Perched as they are atop, Passports from a […]

How I wish I had another chance at, Caroline, I would rub her stomach until, She fell asleep, And sit there some more, Catch her  when the nightmare , Threatened to be too real, I’d tell her stories about the past, about dragons and princesses and, Hero’s, I’d sit still beside her all night and, […]

Friends can bring out the very best in you. A spectacular laugh a, Chocolate in need. Friends are magic creating magic. -short evocative poetry-

We could dance on Gravity, We could burst the Sun, We could be that horror Alien who stole your child, We are born metal touching galaxies though glass, Galileo’s kids seeing through Sombrero, We could look after water, Or it’s facsimile, We could look after Earth.                                                                                                                                                         evocative short poetry

The fish comes steaming, and English is not the only language making sense. Here politics comes with dark green Kale spewing flavor, Kenyans having lunch on the Boulevard, Lakeshore strip, Victoria; Commitment is the idea that momentum cannot disrupt motion, that Committed, one moves forward, Becoming better, Choosing beyond the sound Of Visiting Americans, Prodigal […]

And suddenly there is life; Cross legged, Bug eyed, Oiled and massaged in the temple, Groomed by a priest in, Orange robes and, Fat, fat Ghee smeared on painted plywood, Cheeks, Frantic efforts to recall the past-times of, Gods, Frolicking on Earth, Right next to the toilet, Near the paddocks, In this life. Planes punch […]

The machines do not run us. We are responsible for; Giraffes, Elephants, Rhinos, And Flaura and Fauna. Dried, Sparkly flowers may be intelligent, As the case may be. We may have to look after the galaxy next door, We hope they are thinking the same. Smells orange, like wheat, like oxygen like, Slippers when you […]

  My shoes are not where I left them. There is a dog howling in the distance, And the sound reverberates, Lifting the dew off the dense canopy of trees outside. The bamboo lamp beside the sofa, Sheds dull orange light across the Persian carpet, And I am not casting a shadow. I have, A […]

There must be an angel looking over your shoulder. There must be, even if you Never see her, An Angel. There are creatures on other, Worlds, That look like us but, For the clothing they wear; …delicate, gauze-like materials, that blaze… …yet do no harm. One visited last night, pointing out my story, -where I […]

When you are born, You know that you are, Here to change the world, And it is good, And it’s alright, To do your best. Then, You’re checking the curtains, Just in case, You run out of sunshine. -evocative short poetry-