BioCAT is a mature user facility that supports several types of experiments. One measure of the facility’s scientific impact is the number and quality of the publications produced. As of October 2023, the facility and its users had published more than 600 articles, which had been cited more than 28,000 times with an average number of citations per article around 46.
A list of all BioCAT publications can be found in the APS database
When you publish your science from BioCAT, please follow the guidelines.
Workshops
BioCAT organizes occasional topic focused science workshops (in contrast to our more general training workshops). Videos from lectures at these workshop are listed below
MuscleX 3: Sarcomeric regulation mechanisms in health and disease
- Welcome and introduction to scientific missions at BioCAT by Thomas Irving
- Thick filament regulation in porcine myocardium by Weikang Ma
- The structurally-defined OFF and ON state can be decoupled with biochemically-defined super-relaxed and disordered-relaxed state by Saffie Mohran
- Single-molecule imaging of thick filament regulation in myofibrils by Neil Kad
- In situ structures from relaxed cardiac myofibrils reveal the organization of the muscle thick filament by Davide Tamborrini
- Titin activates myosin filaments in skeletal muscle by switching from an extensible spring to a mechanical rectifier by Caterina Squarci
- Cardiac Troponin T N-domain variant destabilizes the actin interface resulting in disturbed myofilament function by Maicon Landim-Vieira
- Minding the Gap: Myosin Binding Protein C steps over the Interfilament Space by Samantha Harris
- Right Ventricular Cardiomyocyte Sarcomere Dysfunction and Deficient Thick Filament Activation in Human Heart Failure with Right Ventricular Dysfunction by Vivek Jani
- Myosin activator Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle by Farid Moussavi-Harami
Science Highlights
Below is a gallery of a few of BioCAT’s science highlights.
New Resource for the Muscle Diffraction Community
BioCAT staff have just published a review article, Ma & Irving, 2022 Int. J. Mol. Sci. 2022, 23(6), 3052, on the use of small angle X-ray fiber diffraction for studying skeletal and cardiac muscle disease. The article consists of a guided tour of the various diffraction features that can be used to extract specific pieces of information that can be used to provide insights into the structural basis of pathology. The article also contains a comprehensive review of the literature reporting diffraction studies of muscle that illustrates how small angle fiber diffraction has increased our understanding of specific muscle diseases such as hypertrophic cardiomyopathy, dilated cardiomyopathy, and nemaline myopathy.
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What Bacterial Pathogens Can Teach Us about Protein Folding
Protein folding is one of the fascinating unanswered questions in biology. How does an amino acid sequence that is unfolded when it leaves the ribosome manage to fold properly into a highly ordered, lightning-fast enzyme or sturdy structural protein? Why don’t all the proteins in the cell instead just stick to each other, aggregating into a big mess? A unique model system in bacteria may hold some of the answers to these questions. The system involves the study of what are termed autotransporter proteins. These proteins have a highly specialized protein folding process that attracted the attention of a team of researchers who have used this bacterial system as a model to determine what allows these unique proteins to maintain their disordered state in the periplasm. The work includes studies carried out at BioCAT. The authors believe their work will provide important information toward understanding basic questions of protein folding and tests long-held theories about how this remarkable biological process works.
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Relaxation at the Molecular Level
The molecular interactions between the proteins myosin and actin that generate force during muscle contraction are some of the most well-studied molecular interactions in biology. However, there are some congenital skeletal muscle disorders and types of heart failure where relaxation of the muscle, rather than the force generation part of the cycle, appears to be the problem, and there are currently no available treatments that affect relaxation specifically. Recent work conducted at BioCAT used a unique transgenic mouse model, time-resolved small-angle x-ray diffraction, and molecular dynamics simulations to discover more about how myosin and actin interact during skeletal muscle relaxation. This research may help identify new treatments for neuromuscular disorders associated with impaired muscle relaxation kinetics.
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Understanding the Physiology of the Human Heart through the Study of Tarantula Muscles
A research team has found an unlikely source of inspiration for understanding how the human heart works and how we might design better drugs for conditions like hypertrophic cardiomyopathy: tarantulas. The source of nightmares for arachnophobes and the household pets for arachnophiles are inspiring researchers to take new approaches to understanding diseases that alter how heart muscle cells contract and relax. But, before getting to the human heart, there is more to learn about the physiology of tarantula muscles. The researchers set out to understand how contractions in tarantula muscle cells are activated and why are muscle twitches that follow a sustained muscle contraction (post-tetanic) more forceful than those that don’t (pre-tetanic). Their results provide evidence that phosphorylation, the chemical addition of a phosphoryl group (PO3-) to an organic molecule, plays a key role in muscle activation and post-tetanic potentiation (PTP) in tarantula muscles.
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Key Insights into an Inherited Muscle Disease
The gene NEB encodes for the skeletal muscle protein nebulin. Mutations in NEB cause the disease nemaline myopathy, which is one of the more common inherited myopathies. Patients with this muscle disorder have muscle weakness in multiple different parts of their body and can also experience difficulties with feeding or breathing. Currently, there is no cure for nemaline myopathy and treatment options are limited. A team of researchers from the University of Arizona and BioCAT working to provide new insights into the pathogenesis of this skeletal muscle disorder, report a new mouse model of nemaline myopathy that exhibits similar symptoms to those identified in human patients. Importantly, the new mouse model of this disease can be used to test future therapeutics. Future studies are warranted to determine if interventions can relieve disease symptoms in these mice. If successful, such therapeutics could be used for improving the quality of life in human patients.
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Structure-Function Studies Elucidate GPCR-Independent Regulation of G-proteins
Guanine nucleotide binding proteins popularly known as G-proteins, involved in a variety of cellular signal transduction pathways are heterotrimeric proteins consisting of α, β, and γ subunits. Ric8A is known to be both a chaperone for the assembly of the α-subunit of G-proteins, and a Guanine nucleotide Exchange Factor (GEF). McClelland et al., have conducted a detailed structural analysis on the complex between Ric8A and Gαi1 using cryoEM, X-ray crystallography, and SAXS.
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Uncovering Unique Structural Features in Protein Regions Associated with ALS
Prion-like domains (PLDs) have become a topic of interest because of their connection with a variety of debilitating brain diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In fact, mutations in PLDs of some genes have been shown to cause neurodegenerative disease. A recent study using data obtained at BioCAT completed a comprehensive biophysical investigation of PLDs in the protein hnRNPA1 to uncover the major behavioral and structural features of these domains. This meaningful work may lead to discoveries that can help individuals living with such neurodegenerative diseases.
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Sarcomere Structure and Nemaline Myopathy
Nemaline myopathy (NM) is one of the most common congenital non-dystrophic myopathies and is characterized by severe hypotonia, muscle weakness, feeding difficulties, respiratory failure, and the presence of nemaline bodies (rods) in skeletal muscle biopsies. One form of nemaline myopathy is caused by mutations in the KBTBD13 (NEM6) gene. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, super-resolution microscopy, and low angle X-ray diffraction at BioCAT revealed that the impaired muscle relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure.
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Structure-Function Understanding of aGPCR ECRs Critical for Drug-Design
Cellular communication mediated by a variety of cell-surface receptors involves ligand induced conformational changes in the extracellular region (ECR). A variety of drugs such as cetuximab (Epidermal Growth Factor Receptor), etrolizumab (Integrins), and erenumab (calcitonin receptor-like receptor) function by trapping ECRs in specific conformations and have proved to be effective therapeutic agents in several cancers, bowel diseases, and migraine. Leon et al., studied a class of relatively understudied G-protein couple receptors (GPCRs) called adhesion-GPCRs (aGPCRs) which have a structurally unique ECR with a diverse set of mechanistic possibilities.
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Cool Temperatures During Hibernation May Freeze Muscle Contraction to Save Energy
Striated muscle contraction is a highly regulated process that involves an orchestrated series of events within the muscle’s contractile units, which are also known as sarcomeres. In a recent study, researchers studied the effect of low temperature on mammalian skeletal muscle contraction. They found that cooler temperatures reduce force generation by trapping filaments in the muscle sarcomeres in a refractory state that cannot undergo contraction and utilize adenosine triphosphate (ATP). This mechanism provides important insight into how hibernating animals may conserve energy while still allowing vital functions in the body to continue.
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Frustration and Folding of a TIM Barrel Protein
In their continuing endeavor to understand misfolding proteins as part of the etiology of a variety of diseases, the Matthews lab particularly focuses on the different factors that impede a protein’s path from the unfolded state to the global free energy minimum. The complexity of the folding trajectory understandably depends on the size of the protein mostly because of the formation of intermediates many of which often stall the formation of an optimal native conformation.
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Structure of BS Ric8A, a regulator of G-protein Biology
Ric8A is a well-known regulator of G-protein biology and belongs to a class of proteins different from the G protein-coupled receptors (GPCRs), which act via interactions with monomeric Gα subunits as opposed to heterotrimeric Gαβγ proteins. SAXS was used in combination with crystallography and biochemical studies to show that the flexible C-terminal tail is important for the overall stability of Ric8A and the function as a guanine nucleotide exchange factor (GEF).
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Probing the Powering of Contractions in Heart Failure
Current treatments can slow progression of heart failure, but do not address the underlying issues, including specific problems that cause systolic heart failure. In this condition, the heart doesn’t contract vigorously enough in pushing blood into the body’s circulation. But findings at nanometer and millisecond scales, based upon experimental data collected at BioCAT may help improve design of therapies directed at motor proteins to rescue failing hearts.
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New Insights into Traumatic Brain Injury
Traumatic brain injury, or TBI, is often referred to as the “invisible injury” — while on the surface everything seems normal with brain structure, symptoms may present themselves in the behavior of the injured and cannot be explained. This work looked at the effect of controlled amounts of compressive force on rat optic nerves to attempt to identify the changes that occur in otherwise normal looking brain neurons due to the specific impact forces experienced during head trauma. As a result of this ongoing work, researchers have a better understanding of what kind of experience, or injury, leads to what kind of damage in the myelin - helping to visualize injuries based on the smallest force necessary to cause it. This information may be critical to knowing when someone has an injury after an accident but before symptoms emerge, and help supports the decision of when and how to treat them.
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Mechanistic Insights into Insulin Degrading Enzyme from Laminar-Flow SAXS
Insulin Degrading Enzyme (IDE) is known known to be a significant factor in the pathophysiology of conditions such as Diabetes mellitus and Alzheimer’s disease. This paper reveals structural states present during substrate recognition and capture and identifies a potential rate limiting step in the reaction.
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A Target Mutation that Renders a Cancer Drug Ineffective
Mutations in the gene PTPN11, which encodes a common enzyme called SHP2, can result in developmental disorders, such as Noonan Syndrome, and act as oncogenic drivers in patients with certain blood cancers. Due to the well understood role of the enzyme SHP2 in Noonan Syndrome and in tumorigenesis, many companies are currently trying to develop drugs that inhibit the enzyme. Researched investigated what impact mutations to SHP2 may have on the potential efficacy of drugs targeting this enzyme.
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A Super-relaxed Myosin State to Offset Hypertrophic Cardiomyopathy
Researchers investigated the stabilizing action of mavacamten, a cardiac drug currently in phase 3 clinical trials, on the ß-cardiac myosin super-relaxed state and its possible therapeutic effects on hypertrophic cardiomyopathy.
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Unraveling the role of a “nebulous” protein
Nebulin is a protein important to muscle strength, as mutations can cause the muscles in patients with nemaline myopathy disease to be weak, little is known about how it works. Researchers investigated the function of Nebulin in mice and found that it is necessary for generating physiological levels of force.
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Proteins May Prevent Dysfunction and Disease by Relaxing
A new study suggests many proteins remain expanded in the cell, rather than contracting into tight folded shapes.
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Unearthing the Mechanism of the Frank-Starling Law
Recent X-ray diffraction experiments show that the protein titin is critically important for transmitting the stretch-induced signals within the heart’s muscles known to impact the strength with which the heart contracts. This work not only solves a piece of the mystery of how the frank-Starling law determines cardiac function, but provides an avenue for targeted development of drugs to treat heart failure.
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Lafora Disease: A Delicate Solubility Problem
Cells can store up to 55,000 glucose units in water-soluble spheres of branched, polymeric glycogen. This provides ready energy for rapid response to cellular needs but also must be managed carefully because too much glycogen accumulation can activate programmed cell death. This is especially true of neurons, which consume large amounts of glucose but are particularly sensitive to glycogen build-up. One example of what can happen when this basic metabolic process goes awry is observed in Lafora disease, a devastating fatal epilepsy in which mutations in a single key enzyme result in the formation of insoluble glucan inclusion bodies that cause neuronal death. Research conducted at two x-ray beamlines at the U.S. Department of Energy’s Advanced Photon Source (APS), an Office of Science user facility at Argonne solved the structure of the enzyme responsible, the laforin glucan phosphatase. The work has provided important insights into both the basis of Lafora disease and normal glycogen metabolism.
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TAPBR: A Novel Protein Chaperone With a Role in Peptide Editing in Immune Recognition
TAP binding protein, related (TAPbPr), a novel protein chaperone, plays a role in loading peptides onto major histocompatibility class i (mhc i) molecules during the process of immune surveillance. Researchers investigated the biochemical function of TAPbPr, comparing it with tapasin, another chaperone with a similar protein sequence. The results of this study could lead to ways to modulate peptide loading in vaccine design, improving T-cell recognition.
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Combating an Infectious Invader
The investigation of the fungal prion HET-s(218-289) provides insights into the fundamental mechanisms of prion assembly and propagation of its infectious fold, which is made robust by a complex and diverse array of inter and intramolecular structural features. This level of complexity has not been observed in short-peptide amyloids that have been used as prion model systems.
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The cross-bridge spring: cool muscles store elastic energy
The Hawkmoth Manduca sexta is an emerging model system for a wide range of studies in integrative biology. The flight muscles are particularly interesting in that, unlike most insect flight muscle, but like vertebrate skeletal and cardiac muscles, they are a synchronous muscle where each stimulus generates one muscle twitch.
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The Molecular Mechanism of Stretch Activation in Insect Muscle
Flying insects are among the most successful species on our planet. Flight is very metabolically demanding and many insects have found a clever way to reduce energy costs in their flight muscles by employing a process called “stretch activation, which has been recognized since the 1960s as an interesting and physiologically important phenomenon, but a mechanistic explanation has been elusive. Now, research at BioCAT provides another, important step toward a full explanation of stretch activation, which also plays an important role in mammalian cardiac expansion and contraction.
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Packing It In: A New Look at Collagen Fibers
Nature uses collagen everywhere in constructing multicellular animals. There are at least 20 types of collagen, but 80-90% of the collagen in the body consists of types I, II, and III. Collagen type II makes up 50% of all cartilage protein, and is essential in normal formation of such structures as cartilage, the vitreous humor of the eye (the clear gel that fills the space between the lens and the retina of the eyeball of humans and other vertebrates), bones, and teeth. To create these structures, collagen molecules are positioned in arrays called fibrils, producing what are known as the D-periodic fibrillar collagens. Until now, technical limitations prevented accurate structural studies of collagen type II packing. A research team aided by the BioCAT 18- ID beamline and the BioCARS 14-BM-C beamline at the APS has remedied that situation by determining the molecular structure of collagen type II in living tissues.
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The Power of Proteins: Prion Diseases Demystified
It is hard to believe that a single protein can be responsible for the damage inflicted by diseases such as human Creutzfeldt-Jakob and bovine spongiform encephalopathy (Mad Cow Disease). Yet the implicated protein, known as a prion and only about 200 amino acids long, can initiate and propagate a disease cycle just by changing its shape. A collaborative research team has achieved a significant advance in our understanding of the infectious power of the prion protein.
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Getting to Know Cellulose
As humans continue to deplete the Earth’s supply of fossil fuels, finding new sources of energy becomes a priority. Biomass, such as cornhusks left after harvest, is one such alternative energy source. Before efficient use can be made of such materials, understanding how to break down cellulose—the fiber in human nutrition and the main component of much biomass waste—is crucial. With the help of the NE-CAT and BioCAT beamlines at the APS and the SPring-8 (Japan) beamline BL38B1, an international research team from Los Alamos National Laboratory, the University of Tokyo, and the University of Grenoble has identified important new features of cellulose structure. Their work provides important new details that could be used in designing more efficient treatments for cellulosic biomass.
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Filling the Gaps in Collagen Structure
Collagens—we might take them for granted, but without them there would be no way to build tissues of the heart, skin, cornea, or bones. In much the same way that wood is used to frame a house and form a structure for the overlying construction materials, collagens are proteins used in the framing of mammalian tissues, but gaining an accurate picture of their three-dimensional structure in the body has proven more difficult. Thanks to work by a research group based at the Illinois Institute of Technology and using the BioCAT 18-ID beamline at the APS, a complete structure for a collagen molecule—as it actually appears in the extracellular matrix (ECM)—is now available.
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The Correct Signals to Regulate Assembly in Bacteria
By employing x-ray scattering and electron microscopy researchers using the BioCAT beamline were able to describe —in stunning detail— a novel two-component mechanism for assembling a protein associated with bacterial transcription. Their work greatly advances our understanding of what happens in normal and, by inference, diseased cells.
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Storing the Power to Fly
Fruit flies beat their wings faster than their cellular powerplants can generate the energy needed for flapping. To resolve this energetic discrepancy, researchers used the BioCAT beamline to obtain a series of x-ray photographs that revealed the flies’ secret: A muscle protein used to power wings acts like a spring, storing energy while stretched before snapping back. Not only did this finding surprise researchers who study muscle, but the results might also help scientists better understand the human heart.
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