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Atomic Force Microscopy of Biomembranes
Published in Qiu-Xing Jiang, New Techniques for Studying Biomembranes, 2020
Yi Ruan, Lorena Redondo-Morata, Simon Scheuring
Besides imaging, another major application of AFM is force spectroscopy (AFM-FS), a method for direct measurement of tip-sample interaction forces as a function of the displacement between the tip and the sample, thus force spectroscopy allowed to measure ligand-receptor binding and protein unfolding through recording of the forces experienced by the cantilever during tip approach-retract cycles. Spectrin, a long, thin, flexible rod-shaped protein that is ~100 nm in length, is a cytoskeletal protein and a peripheral membrane protein. It is the principal component of the cytoskeleton that underlies the cell membrane, the paradigm example of which is the red blood cell (RBC) membrane. It maintains the structural integrity and biconcave shape of the RBC membrane. It is located at the inner face of the plasma membrane, making connections between membrane anchors and the actin cortex meshwork and between actin filaments. Compared to conventional AFM-FS,52,53 HS-AFM-FS with short cantilevers allows unfolding spectrin proteins at velocities up to 10−2 m/s.54 This is faster than conventional AFM-FS by several orders of magnitude and reaches a rate comparable to steered molecular dynamics simulations (SMDS).55,56 HS-AFM-FS combined with SMDS spectrin unfolding, revealed the protein’s mechanical properties, multiple unfolding pathways, intermediate folding states, etc.
Hemolytic Anemia Associated with Red Cell Membrane Defects
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
HS is produced by mutations in the genes encoding several different component proteins of the membrane skeleton (Fig. 1). The most frequent mutations that give rise to HS affect the genes for ankyrin and band 3 (anion channel). Mutations also occur in α spectrin, β spectrin, and protein 4.2 (pallidin). The final common pathophysiologic pathway produced by most HS mutations is spectrin deficiency. Spectrin deficiency leads to membrane loss and spherocytosis. It is a consistent characteristic of HS that most hemolysis occurs selectively in the spleen.
Inherited Disorders of Red Cell Membrane Proteins
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
The other end of the spectrin dimer contains the binding site for protein 4.1.35 This interaction augments the binding of spectrin to actin, allowing for extension of the three-dimensional spectrin network, enhancing the stability of the membrane. Spectrin defective in the protein 4.1 binding region has been found in hereditary spherocytosis, as will be discussed later.
Emerging therapeutic targets for cardiac hypertrophy
Published in Expert Opinion on Therapeutic Targets, 2022
Alexander J. Winkle, Drew M. Nassal, Rebecca Shaheen, Evelyn Thomas, Shivangi Mohta, Daniel Gratz, Seth H. Weinberg, Thomas J. Hund
The significance of achieving balanced STAT3 activity has also emerged in investigations for the cytoskeletal protein βIV-spectrin. βIV-spectrin is an adapter protein, linking membrane associated proteins with the cytoskeleton [92]. Initially characterized as a passive element for maintaining membrane shape and elasticity, our understanding of βIV-spectrin has expanded to include dynamic roles in protein localization and signal transduction, with particular focus on cardiac fibrosis and hypertrophy [65,93,94]. In myocytes, βIV-spectrin localizes to the intercalated disc, where it contributes to localization of CaMKII and STAT3 within the same domain (Figure 2) [65]. It was identified that cardiac stress induces the degradation of βIV-spectrin in response to activated CaMKII activity, contributing to more diffuse cytosolic and nuclear localization and heightened STAT3 transcriptional activity. Genetic ablation of the βIV-spectrin/CaMKII interaction, however, protected βIV-spectrin from TAC-induced degradation, preserving its, and consequently STAT3, signal at the intercalated disc, effectively limiting STAT3 activity and related gene expression. This contributed to significantly reduced fibrosis in response to TAC, but most interestingly led to sustained concentric hypertrophy and cardiac function, whereas WT mice developed decompensated heart failure (eccentric hypertrophy) characterized by ventricular dilation and impaired contractility.
Targeted next-generation sequencing identified a novel ANK1 mutation associated with hereditary spherocytosis in a Chinese family
Published in Hematology, 2019
Qing Sun, Yao Xie, Penghui Wu, Shuo Li, Ying Hua, Xintian Lu, Weihong Zhao
HS represents a group of congenital diseases characterized by the presence of spherical erythrocytes in peripheral blood smears [12]. Moreover, HS is the most common cause of congenital haemolytic anaemia due to membrane protein defects [13]. The ANK1 gene is located on chromosome 8p11.1 and encodes several alternatively spliced isoforms [14]. Erythroid ankyrin is the predominant protein encoded by ANK1 in red blood cells. Because ankyrin attaches β-spectrin to the band 3 protein, lack of ankyrin leads to a proportional and secondary decrease in spectrin assembly on the membrane, in spite of normal spectrin synthesis [15]. Defects in these proteins lead to a decrease in the erythrocyte surface area, a spherical shape of erythrocytes and, in particular, loss of membrane elasticity and mechanical stability [16].
A novel EPB41 p.Trp704* mutation in a Korean patient with hereditary elliptocytosis: a case report
Published in Hematology, 2020
Soyoung Shin, Kyung-Ah Hwang, Kyuhyun Paik, Joonhong Park
HE occurs in 0.3–0.5 per 1000 newborns, and patients are asymptomatic in about 90% of cases [9]. Approximately 95% of patients with HE have a mutation in genes responsible for α- and β-spectrin expression, i.e. polypeptides which in tetrameric form compose the basis of the cell cytoskeleton [6]. Mutations associated with the protein 4.1 and glycophorin C are rare [6]. Patients with a mutation on only one allele are asymptomatic, while in cases when it is bilateral suffer moderate or more severe hemolytic anemia [6,9]. In addition, the hereditary nature of the disorder is also supported by the absence of elements indicating other conditions that are associated with the presence of elliptocytes, such as deficiencies in iron, folic acid, or vitamin B12 [9].