Paralemmin-1 Controls the Nanoarchitecture of the Neuronal Submembrane Cytoskeleton

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2025 Mar 7

PMID 40053592

Authors

Victor Macarron-Palacios

Jasmine Hubrich

Maria Augusta do Rego Barros Fernandes Lima

Nicole G Metzendorf

Simon Kneilmann

Marleen Trapp

Claudio Acuna

Annarita Patrizi

Elisa DEste

Manfred W Kilimann

Affiliations

Soon will be listed here.

Abstract

The submembrane cytoskeleton of neurons displays a highly ordered 190-nanometer periodic actin-spectrin lattice, the membrane-associated periodic skeleton (MPS). It is involved in mechanical resilience, signaling, and action potential transmission. Here, we identify paralemmin-1 (Palm1) as a component and regulator of the MPS. Palm1 binds to the amino-terminal region of βII-spectrin, and MINFLUX microscopy localizes it in close proximity (<20 nanometers) to the actin-capping protein and MPS component adducin. Combining overexpression, knockout, and rescue experiments, we observe that the expression level of Palm1 controls the degree of periodicity of the MPS and also affects the electrophysiological properties of neurons. A single amino acid mutation (W54A) in Palm1 abolishes the MPS binding and remodeling activities of Palm1. Our findings identify Palm1 as a protein specifically dedicated to organizing the MPS and will advance the understanding of the assembly and plasticity of the actin-spectrin submembrane skeleton in general.

References

Ho K, Patrizi A . Assessment of common housekeeping genes as reference for gene expression studies using RT-qPCR in mouse choroid plexus. Sci Rep. 2021; 11(1):3278. PMC: 7870894. DOI: 10.1038/s41598-021-82800-5. View

Doench J, Fusi N, Sullender M, Hegde M, Vaimberg E, Donovan K . Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat Biotechnol. 2016; 34(2):184-191. PMC: 4744125. DOI: 10.1038/nbt.3437. View

He Z, Wu K, Xie W, Chen J . Case report and literature review: A pathogenic missense variant in gene caused rapid progression to end-stage renal disease. Front Pediatr. 2022; 10:930258. PMC: 9452832. DOI: 10.3389/fped.2022.930258. View

Xu K, Zhong G, Zhuang X . Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science. 2012; 339(6118):452-6. PMC: 3815867. DOI: 10.1126/science.1232251. View

Brown J, Bullitt E, Sriswasdi S, Harper S, Speicher D, McKnight C . The Physiological Molecular Shape of Spectrin: A Compact Supercoil Resembling a Chinese Finger Trap. PLoS Comput Biol. 2015; 11(6):e1004302. PMC: 4466138. DOI: 10.1371/journal.pcbi.1004302. View

Arstikaitis P, Gauthier-Campbell C, Carolina Gutierrez Herrera R, Huang K, Levinson J, Murphy T . Paralemmin-1, a modulator of filopodia induction is required for spine maturation. Mol Biol Cell. 2008; 19(5):2026-38. PMC: 2366842. DOI: 10.1091/mbc.e07-08-0802. View

Avery A, Thomas D, Hays T . β-III-spectrin spinocerebellar ataxia type 5 mutation reveals a dominant cytoskeletal mechanism that underlies dendritic arborization. Proc Natl Acad Sci U S A. 2017; 114(44):E9376-E9385. PMC: 5676893. DOI: 10.1073/pnas.1707108114. View

Lin A, Prochniewicz E, James Z, Svensson B, Thomas D . Large-scale opening of utrophin's tandem calponin homology (CH) domains upon actin binding by an induced-fit mechanism. Proc Natl Acad Sci U S A. 2011; 108(31):12729-33. PMC: 3150896. DOI: 10.1073/pnas.1106453108. View

Zhou D, Lambert S, Malen P, Carpenter S, Boland L, Bennett V . AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J Cell Biol. 1998; 143(5):1295-304. PMC: 2133082. DOI: 10.1083/jcb.143.5.1295. View

10.

Hu B, Copeland N, Gilbert D, Jenkins N, Kilimann M . The paralemmin protein family: identification of paralemmin-2, an isoform differentially spliced to AKAP2/AKAP-KL, and of palmdelphin, a more distant cytosolic relative. Biochem Biophys Res Commun. 2001; 285(5):1369-76. DOI: 10.1006/bbrc.2001.5329. View

11.

Willems J, de Jong A, Scheefhals N, Mertens E, Catsburg L, Poorthuis R . ORANGE: A CRISPR/Cas9-based genome editing toolbox for epitope tagging of endogenous proteins in neurons. PLoS Biol. 2020; 18(4):e3000665. PMC: 7176289. DOI: 10.1371/journal.pbio.3000665. View

12.

Rain J, Legrain P . Toward a functional analysis of the yeast genome through exhaustive two-hybrid screens. Nat Genet. 1997; 16(3):277-82. DOI: 10.1038/ng0797-277. View

13.

Efimova N, Korobova F, Stankewich M, Moberly A, Stolz D, Wang J . βIII Spectrin Is Necessary for Formation of the Constricted Neck of Dendritic Spines and Regulation of Synaptic Activity in Neurons. J Neurosci. 2017; 37(27):6442-6459. PMC: 5511878. DOI: 10.1523/JNEUROSCI.3520-16.2017. View

14.

Korsgren C, Lux S . The carboxyterminal EF domain of erythroid alpha-spectrin is necessary for optimal spectrin-actin binding. Blood. 2010; 116(14):2600-7. PMC: 2953892. DOI: 10.1182/blood-2009-12-260612. View

15.

Lorenzo D, Edwards R, Slavutsky A . Spectrins: molecular organizers and targets of neurological disorders. Nat Rev Neurosci. 2023; 24(4):195-212. PMC: 10598481. DOI: 10.1038/s41583-022-00674-6. View

16.

Fukami K, Sawada N, Endo T, Takenawa T . Identification of a phosphatidylinositol 4,5-bisphosphate-binding site in chicken skeletal muscle alpha-actinin. J Biol Chem. 1996; 271(5):2646-50. DOI: 10.1074/jbc.271.5.2646. View

17.

Galiano M, Jha S, Ho T, Zhang C, Ogawa Y, Chang K . A distal axonal cytoskeleton forms an intra-axonal boundary that controls axon initial segment assembly. Cell. 2012; 149(5):1125-39. PMC: 3361702. DOI: 10.1016/j.cell.2012.03.039. View

18.

Han B, Zhou R, Xia C, Zhuang X . Structural organization of the actin-spectrin-based membrane skeleton in dendrites and soma of neurons. Proc Natl Acad Sci U S A. 2017; 114(32):E6678-E6685. PMC: 5559029. DOI: 10.1073/pnas.1705043114. View

19.

Young P, Gautel M . The interaction of titin and alpha-actinin is controlled by a phospholipid-regulated intramolecular pseudoligand mechanism. EMBO J. 2000; 19(23):6331-40. PMC: 305858. DOI: 10.1093/emboj/19.23.6331. View

20.

Dubey S, Bhembre N, Bodas S, Veer S, Ghose A, Callan-Jones A . The axonal actin-spectrin lattice acts as a tension buffering shock absorber. Elife. 2020; 9. PMC: 7190353. DOI: 10.7554/eLife.51772. View