# SEPTIN4

## Overview
SEPTIN4 is a gene that encodes the protein septin 4, a member of the septin family of GTP-binding proteins. Septin 4 is involved in a variety of cellular processes, including cytokinesis, vesicle trafficking, and cytoskeletal organization, which are essential for maintaining cell shape and facilitating cell division (Sun2012Expression). As a cytoskeletal protein, septin 4 plays a significant role in neuronal migration and morphogenesis, particularly during corticogenesis, where it forms complexes with other septins to support the formation of the leading process in migrating neurons (Shinoda2010Septin). SEPTIN4 is also implicated in neurodegenerative diseases, such as Parkinson's disease, where it interacts with α-synuclein in Lewy bodies, potentially offering a protective role against neurotoxicity (Ihara2007Sept4; Ihara2003Association). Additionally, SEPTIN4 is involved in apoptotic pathways and has been identified as a fusion partner in certain leukemias, underscoring its relevance in both neurobiology and oncology (Neubauer2017The; Zhao2020Septin4).

## Structure
SEPTIN4 is a member of the septin family of GTP-binding proteins, characterized by a conserved GTPase domain. The primary structure of SEPTIN4 includes a GTPase domain, which is crucial for its function in cellular processes such as cytokinesis and vesicle trafficking (Garcia2007An). The secondary structure of SEPTIN4 features a combination of alpha-helices and beta-sheets, with a significant transition from an alpha-helical structure to a beta-strand-rich intermediate during thermal unfolding (Garcia2007An). This intermediate structure is stable between 30 and 42 °C and is associated with amyloid-like aggregation (Garcia2007An).

The tertiary structure of SEPTIN4 involves a conserved septin core, which is essential for its stability and function. SEPTIN4 can form hetero-oligomeric complexes, contributing to its quaternary structure. It is capable of forming homo-filaments and amyloid-like aggregates, which are significant in the context of neurodegenerative diseases (Neubauer2017The).

SEPTIN4 has eight isoforms, with isoform 1 being extensively studied for its role in sperm motility and structure (Vickram2021Identification). The absence of experimental 3D structures has led to the use of in-silico modeling to predict its structure, providing insights into its function and potential as a biomarker for male infertility (Vickram2021Identification).

## Function
SEPTIN4 is a member of the septin family of GTP-binding proteins, which are involved in various cellular processes, including cytokinesis, vesicle trafficking, and cell cycle regulation. Septins, including SEPTIN4, form hetero-oligomeric complexes and filaments that contribute to cytoskeletal organization, playing a crucial role in maintaining cell shape and facilitating cell division (Sun2012Expression).

In the context of neuronal cells, SEPTIN4 is implicated in neuronal migration and morphogenesis during corticogenesis. It interacts with SEPTIN14 to form a complex that is essential for the formation of the leading process in migrating neurons. Knockdown experiments have shown that reducing SEPTIN4 expression results in shorter leading processes in neurons, indicating its role in process formation rather than cell-autonomous polarity formation (Shinoda2010Septin). SEPTIN4 is also involved in the proper positioning of neurons during cortical development, as its knockdown disrupts neuronal migration (Shinoda2010Septin).

SEPTIN4 is active in the cytoplasm, where it contributes to cytoskeletal dynamics, which are crucial for directed neuronal migration and morphological changes. This protein may interact with cytoskeleton-regulating proteins or the cytoskeleton itself to facilitate these processes (Shinoda2010Septin).

## Clinical Significance
SEPTIN4 is implicated in several neurodegenerative diseases, particularly Parkinson's disease (PD) and other synucleinopathies. In PD, SEPTIN4 is found in Lewy bodies, which are pathological hallmarks of the disease. Its interaction with α-synuclein, a protein that aggregates in PD, is crucial for the formation of these inclusions. SEPTIN4 co-localizes with α-synuclein in these aggregates, and its deficiency is associated with increased α-synuclein aggregation and neurotoxicity, suggesting a protective role against neurodegeneration (Ihara2007Sept4; Ihara2003Association).

SEPTIN4 is also involved in dopaminergic neurotransmission. In PD patients, SEPTIN4 levels are reduced in the striatum, leading to diminished dopamine turnover and contributing to the disease's motor symptoms. This reduction is linked to a decrease in presynaptic proteins essential for dopamine release and reuptake (Ihara2007Sept4).

Beyond neurodegenerative diseases, SEPTIN4 is implicated in cancer. It has been identified as a fusion partner with myeloid-lymphoid leukemia (MLL) genes, indicating a potential role in leukemia. The misregulation of SEPTIN4 and other septins is associated with various diseases, highlighting their importance in cellular functions and disease mechanisms (Neubauer2017The).

## Interactions
SEPTIN4, a member of the septin family, is involved in various protein interactions that play crucial roles in cellular processes. It interacts with the pro-apoptotic protein BAX, promoting apoptosis in human colon cancer cells. This interaction is enhanced under doxorubicin treatment, suggesting SEPTIN4's role in facilitating apoptosis through mitochondrial outer membrane permeabilization (Zhao2020Septin4). SEPTIN4 also interacts with XIAP, an inhibitor of apoptosis, and this interaction is significant in the regulation of apoptotic pathways (Desterke2019Proteinprotein).

In the context of neuronal migration, SEPTIN4 interacts with SEPTIN14, where both proteins are essential for proper cortical neuronal migration and process formation during development (Shinoda2010Septin). SEPTIN4 is also involved in septin-septin interactions, forming both homotypic and heterotypic assemblies with other septins such as SEPT5 and SEPT8. These interactions are crucial for septin complex targeting within the cytosol (MARTÍNEZ2004Human). SEPTIN4's ability to substitute for SEPT2 in the SEPT2-6-7 complex highlights its role in septin filament formation and stability (Neubauer2017The).


## References


[1. (Vickram2021Identification) A. S. Vickram, K. Anbarasu, Palanivelu Jeyanthi, G. Gulothungan, R. Nanmaran, S. Thanigaivel, T. B. Sridharan, and Karunakaran Rohini. Identification and structure prediction of human septin-4 as a biomarker for diagnosis of asthenozoospermic infertile patients—critical finding toward personalized medicine. Frontiers in Medicine, December 2021. URL: http://dx.doi.org/10.3389/fmed.2021.723019, doi:10.3389/fmed.2021.723019. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fmed.2021.723019)

[2. (Garcia2007An) Wanius Garcia, Ana Paula Ulian de Araújo, Flávio Lara, Debora Foguel, Manami Tanaka, Tomoo Tanaka, and Richard Charles Garratt. An intermediate structure in the thermal unfolding of the gtpase domain of human septin 4 (sept4/bradeion-β) forms amyloid-like filaments in vitro. Biochemistry, 46(39):11101–11109, September 2007. URL: http://dx.doi.org/10.1021/bi700702w, doi:10.1021/bi700702w. This article has 23 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi700702w)

[3. (Desterke2019Proteinprotein) Christophe Desterke and Ama Gassama-Diagne. Protein-protein interaction analysis highlights the role of septins in membrane enclosed lumen and mrna processing. Advances in Biological Regulation, 73:100635, August 2019. URL: http://dx.doi.org/10.1016/j.jbior.2019.100635, doi:10.1016/j.jbior.2019.100635. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.jbior.2019.100635)

[4. (MARTÍNEZ2004Human) Constantino MARTÍNEZ, Miguel A. SANJUAN, Judith A. DENT, Lars KARLSSON, and Jerry WARE. Human septin–septin interactions as a prerequisite for targeting septin complexes in the cytosol. Biochemical Journal, 382(3):783–791, September 2004. URL: http://dx.doi.org/10.1042/bj20040372, doi:10.1042/bj20040372. This article has 40 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1042/bj20040372)

[5. (Ihara2007Sept4) Masafumi Ihara, Nobuyuki Yamasaki, Akari Hagiwara, Ai Tanigaki, Ayumi Kitano, Rie Hikawa, Hidekazu Tomimoto, Makoto Noda, Masashi Takanashi, Hideo Mori, Nobutaka Hattori, Tsuyoshi Miyakawa, and Makoto Kinoshita. Sept4, a component of presynaptic scaffold and lewy bodies, is required for the suppression of α-synuclein neurotoxicity. Neuron, 53(4):519–533, February 2007. URL: http://dx.doi.org/10.1016/j.neuron.2007.01.019, doi:10.1016/j.neuron.2007.01.019. This article has 135 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.neuron.2007.01.019)

[6. (Shinoda2010Septin) Tomoyasu Shinoda, Hidenori Ito, Kaori Sudo, Ikuko Iwamoto, Rika Morishita, and Koh-ichi Nagata. Septin 14 is involved in cortical neuronal migration via interaction with septin 4. Molecular Biology of the Cell, 21(8):1324–1334, April 2010. URL: http://dx.doi.org/10.1091/mbc.e09-10-0869, doi:10.1091/mbc.e09-10-0869. This article has 61 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1091/mbc.e09-10-0869)

[7. (Zhao2020Septin4) Xin Zhao, Hao Feng, Yang Wang, Yanmei Wu, Qiqiang Guo, Yanling Feng, Mengtao Ma, Wendong Guo, Xiaoyu Song, Ying Zhang, Shuai Han, and Liu Cao. Septin4 promotes cell death in human colon cancer cells by interacting with bax. International Journal of Biological Sciences, 16(11):1917–1928, 2020. URL: http://dx.doi.org/10.7150/ijbs.44429, doi:10.7150/ijbs.44429. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.7150/ijbs.44429)

[8. (Neubauer2017The) Katharina Neubauer and Barbara Zieger. The mammalian septin interactome. Frontiers in Cell and Developmental Biology, February 2017. URL: http://dx.doi.org/10.3389/fcell.2017.00003, doi:10.3389/fcell.2017.00003. This article has 79 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fcell.2017.00003)

[9. (Sun2012Expression) Xiaolei Sun, Yanan Yang, Dandan Zhu, Hongyan Qian, Yinong Duan, Xingxin He, Xijuan Gu, Wei Sun, and Ying Zhu. Expression of septin4 in human hepatic stellate cells lx-2 stimulated by lps. Inflammation, 36(3):539–548, November 2012. URL: http://dx.doi.org/10.1007/s10753-012-9575-x, doi:10.1007/s10753-012-9575-x. This article has 10 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s10753-012-9575-x)

[10. (Ihara2003Association) Masafumi Ihara, Hidekazu Tomimoto, Hitoshi Kitayama, Yoko Morioka, Ichiro Akiguchi, Hiroshi Shibasaki, Makoto Noda, and Makoto Kinoshita. Association of the cytoskeletal gtp-binding protein sept4/h5 with cytoplasmic inclusions found in parkinson’s disease and other synucleinopathies. Journal of Biological Chemistry, 278(26):24095–24102, June 2003. URL: http://dx.doi.org/10.1074/jbc.m301352200, doi:10.1074/jbc.m301352200. This article has 109 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m301352200)